NCBI Conserved Domain Search

calmodulin; Provisional

Pssm-ID: 185504 [Multi-domain] Cd Length: 149 Bit Score: 105.23 E-value: 6.01e-29

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  46 IAENLSEEEIKGLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVtaTMHQHKL- 124
Cdd:PTZ00184    1 MADQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFL--TLMARKMk 78

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183 125 --ERDEHLYKAFQYFDKDHSGFITRDELETAMKEYGMG-DDATIREIISEVDTDNDGRINYEEFCTMMRS 191
Cdd:PTZ00184   79 dtDSEEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKlTDEEVDEMIREADVDGDGQINYEEFVKMMMS 148

centrin; Provisional

Pssm-ID: 185503 [Multi-domain] Cd Length: 158 Bit Score: 93.22 E-value: 3.66e-24

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  50 LSEEEIKGLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFV-TATMHQHKLERDE 128
Cdd:PTZ00183   11 LTEDQKKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLdIMTKKLGERDPRE 90

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2526894183 129 HLYKAFQYFDKDHSGFITRDELETAMKEYGMG-DDATIREIISEVDTDNDGRINYEEFCTMMR 190
Cdd:PTZ00183   91 EILKAFRLFDDDKTGKISLKNLKRVAKELGETiTDEELQEMIDEADRNGDGEISEEEFYRIMK 153

Ca2+-binding protein, EF-hand superfamily [Signal transduction mechanisms];

Pssm-ID: 444056 [Multi-domain] Cd Length: 137 Bit Score: 89.85 E-value: 3.62e-23

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  52 EEEIKGLKAVFTNIDTDKSGTITYEELktglarlgSRLSEAEVEQLMEAADVDGNGTIDYIEFVTATMHQHKLERDEHLY 131
Cdd:COG5126     1 DLQRRKLDRRFDLLDADGDGVLERDDF--------EALFRRLWATLFSEADTDGDGRISREEFVAGMESLFEATVEPFAR 72

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183 132 KAFQYFDKDHSGFITRDELETAMKEYGMGDDAtIREIISEVDTDNDGRINYEEFCTMMRS 191
Cdd:COG5126    73 AAFDLLDTDGDGKISADEFRRLLTALGVSEEE-ADELFARLDTDGDGKISFEEFVAAVRD 131

EF-hand, calcium binding motif, found in homologs of mammalian apoptosis-linked gene 2 protein (ALG-2); The family includes some homologs of mammalian apoptosis-linked gene 2 protein (ALG-2) mainly found in lower eukaryotes, such as a parasitic protist Leishmarua major and a cellular slime mold Dictyostelium discoideum. These homologs contains five EF-hand motifs. Due to the presence of unfavorable residues at the Ca2+-coordinating positions, their non-canonical EF4 and EF5 hands may not bind Ca2+. Two Dictyostelium PEF proteins are the prototypes of this family. They may bind to cytoskeletal proteins and/or signal-transducing proteins localized to detergent-resistant membranes named lipid rafts, and occur as monomers or weak homo- or heterodimers like ALG-2. They can serve as a mediator for Ca2+ signaling-related Dictyostehum programmed cell death (PCD).

Pssm-ID: 320060 [Multi-domain] Cd Length: 163 Bit Score: 79.57 E-value: 7.09e-19

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  58 LKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFvtATMHQHKLErdehLYKAFQYF 137
Cdd:cd16185     2 LRQWFRAVDRDRSGSIDVNELQKALAGGGLLFSLATAEKLIRMFDRDGNGTIDFEEF--AALHQFLSN----MQNGFEQR 75

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 2526894183 138 DKDHSGFITRDELETAMKEYGMG-DDATIREIISEVDTDNDGRINYEEF 185
Cdd:cd16185    76 DTSRSGRLDANEVHEALAASGFQlDPPAFQALFRKFDPDRGGSLGFDDY 124

EF-hand, calcium binding motif; A diverse superfamily of calcium sensors and calcium signal modulators; most examples in this alignment model have 2 active canonical EF hands. Ca2+ binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers.

Pssm-ID: 238008 [Multi-domain] Cd Length: 63 Bit Score: 71.04 E-value: 8.69e-17

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183 132 KAFQYFDKDHSGFITRDELETAMKEYGMG-DDATIREIISEVDTDNDGRINYEEFCTMMR 190
Cdd:cd00051     4 EAFRLFDKDGDGTISADELKAALKSLGEGlSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

EF-hand domain pair;

Pssm-ID: 463900 [Multi-domain] Cd Length: 67 Bit Score: 69.20 E-value: 4.65e-16

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2526894183 127 DEHLYKAFQYFDKDHSGFITRDELETAMKEYGMG---DDATIREIISEVDTDNDGRINYEEFCTMMR 190
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGeplSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

EF-hand motif found in eukaryotic phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11) isozymes; PI-PLC isozymes are signaling enzymes that hydrolyze the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. This family corresponds to the four EF-hand motifs containing PI-PLC isozymes, including PI-PLC-beta (1-4), -gamma (1-2), -delta (1,3,4), -epsilon (1), -zeta (1), eta (1-2). Lower eukaryotes such as yeast and slime molds contain only delta-type isozymes. In contrast, other types of isoforms present in higher eukaryotes. This family also includes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase 1 (PLC1) from fungi. Some homologs from plants contain only two atypical EF-hand motifs and they are not included. All PI-PLC isozymes except sperm-specific PI-PLC-zeta share a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C2 domain. PI-PLC-zeta lacks the PH domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Most of EF-hand motifs found in PI-PLCs consist of a helix-loop-helix structure, but lack residues critical to metal binding. Moreover, the EF-hand region of most of PI-PLCs may have an important regulatory function, but it has yet to be identified. However, PI-PLC-zeta is a key exception. It is responsible for Ca2+ oscillations in fertilized oocytes and exhibits a high sensitivity to Ca2+ mediated through its EF-hand domain. In addition, PI-PLC-eta2 shows a canonical EF-loop directing Ca2+-sensitivity and thus can amplify transient Ca2+ signals. Also it appears that PI-PLC-delta1 can regulate the binding of PH domain to PIP2 in a Ca2+-dependent manner through its functionally important EF-hand domains. PI-PLCs can be activated by a variety of extracellular ligands, such as growth factors, hormones, cytokines and lipids. Their activation has been implicated in tumorigenesis and/or metastasis linked to migration, proliferation, growth, inflammation, angiogenesis and actin cytoskeleton reorganization. PI-PLC-beta isozymes are activated by G-protein coupled receptor (GPCR) through different mechanisms. However, PI-PLC-gamma isozymes are activated by receptor tyrosine kinase (RTK), such as Rho and Ras GTPases. In contrast, PI-PLC-epsilon are activated by both GPCR and RTK. PI-PLC-delta1 and PLC-eta 1 are activated by GPCR-mediated calcium mobilization. The activation mechanism for PI-PLC-zeta remains unclear.

Pssm-ID: 320029 [Multi-domain] Cd Length: 137 Bit Score: 69.23 E-value: 3.29e-15

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  58 LKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVTATMhqhKLERDEHLYKAFQYF 137
Cdd:cd15898     2 LRRQWIKADKDGDGKLSLKEIKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELYK---SLTERPELEPIFKKY 78

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 2526894183 138 DKDHSGFITRDELETAMKE--YGMGDDATIREIISEVDTD-NDGRINYEEFCTMMRS 191
Cdd:cd15898    79 AGTNRDYMTLEEFIRFLREeqGENVSEEECEELIEKYEPErENRQLSFEGFTNFLLS 135

Ca2+-binding protein, EF-hand superfamily [Signal transduction mechanisms];

Pssm-ID: 444056 [Multi-domain] Cd Length: 137 Bit Score: 68.28 E-value: 6.03e-15

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  58 LKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVTAtMHQHKLeRDEHLYKAFQYF 137
Cdd:COG5126    35 WATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEFRRL-LTALGV-SEEEADELFARL 112

                          90       100
                  ....*....|....*....|
gi 2526894183 138 DKDHSGFITRDELETAMKEY 157
Cdd:COG5126   113 DTDGDGKISFEEFVAAVRDY 132

EF-hand, calcium binding motif; A diverse superfamily of calcium sensors and calcium signal modulators; most examples in this alignment model have 2 active canonical EF hands. Ca2+ binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers.

Pssm-ID: 238008 [Multi-domain] Cd Length: 63 Bit Score: 65.65 E-value: 1.15e-14

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  58 LKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVTA 117
Cdd:cd00051     2 LREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLEL 61

Penta-EF hand, calcium binding motifs, found in Group I PEF proteins; The family corresponds to Group I PEF proteins that have been found not only in higher animals but also in lower animals, plants, fungi and protists. Group I PEF proteins include apoptosis-linked gene 2 protein (ALG-2), peflin and similar proteins. ALG-2, also termed programmed cell death protein 6 (PDCD6), is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination. Peflin is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+.

Pssm-ID: 320055 [Multi-domain] Cd Length: 164 Bit Score: 67.94 E-value: 1.55e-14

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  58 LKAVFTNIDTDKSGTITYEELKTGLAR-LGSRLSEAEVEQLMEAADVDGNGTIDYIEFVtatmhqhKL-ERDEHLYKAFQ 135
Cdd:cd16180     2 LRRIFQAVDRDRSGRISAKELQRALSNgDWTPFSIETVRLMINMFDRDRSGTINFDEFV-------GLwKYIQDWRRLFR 74

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2526894183 136 YFDKDHSGFITRDELETAMKEYGMG-DDATIREIISEVDTDNDGRINYEEF 185
Cdd:cd16180    75 RFDRDRSGSIDFNELQNALSSFGYRlSPQFVQLLVRKFDRRRRGSISFDDF 125

EF-hand, calcium binding motif, found in peflin and similar proteins; Peflin, also termed penta-EF hand (PEF) protein with a long N-terminal hydrophobic domain, or penta-EF hand domain-containing protein 1, is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. In lower vertebrates, peflin may interact with transient receptor potential N (TRPN1), suggesting a potential role of peflin in fast transducer channel adaptation.

Pssm-ID: 320059 [Multi-domain] Cd Length: 165 Bit Score: 66.52 E-value: 6.19e-14

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  62 FTNIDTDKSGTITYEELKTGLARL-GSRLSEAEVEQLMEAADVDGNGTIDYIEFvtatmhqhklerdEHLYK-------A 133
Cdd:cd16184     6 FQAVDRDRSGKISAKELQQALVNGnWSHFNDETCRLMIGMFDKDKSGTIDIYEF-------------QALWNyiqqwkqV 72

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2526894183 134 FQYFDKDHSGFITRDELETAMKEygMG---DDATIREIISEVDTDNDGRINYEEF---CTMMRS 191
Cdd:cd16184    73 FQQFDRDRSGSIDENELHQALSQ--MGyrlSPQFVQFLVSKYDPRARRSLTLDQFiqvCVQLQS 134

XopAW family type III secretion system calcium-binding effector;

Pssm-ID: 469301 [Multi-domain] Cd Length: 227 Bit Score: 65.86 E-value: 3.19e-13

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  58 LKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVTAT-------MHQHKLERDEHL 130
Cdd:NF041410   29 QKQLFAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAApppppppDQAPSTELADDL 108

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2526894183 131 YKAfqyFDKDHSGFITRDELETAMKEYGMGDDATirEIISEVDTDNDGRINYEEFctmmRSGMQQQG 197
Cdd:NF041410  109 LSA---LDTDGDGSISSDELSAGLTSAGSSADSS--QLFSALDSDGDGSVSSDEL----AAALQPPP 166

EF-hand, calcium binding motif, found in apoptosis-linked gene 2 protein (ALG-2) and similar proteins; ALG-2, also termed programmed cell death protein 6 (PDCD6), or probable calcium-binding protein ALG-2, is one of the prototypic members of the penta EF-hand protein family. It is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. ALG-2 acts as a pro-apoptotic factor participating in T cell receptor-, Fas-, and glucocorticoid-induced programmed cell death, and also serves as a useful molecular marker for the prognosis of cancers. Moreover, ALG-2 functions as a calcium ion sensor at endoplasmic reticulum (ER) exit sites, and modulates ER-stress-stimulated cell death and neuronal apoptosis during organ formation. Furthermore, ALG-2 can mediate the pro-apoptotic activity of cisplatin or tumor necrosis factor alpha (TNFalpha) through the down-regulation of nuclear factor-kappaB (NF-kappaB) expression. It also inhibits angiogenesis through PI3K/mTOR/p70S6K pathway by interacting of vascular endothelial growth factor receptor-2 (VEGFR-2). In addition, nuclear ALG-2 may participate in the post-transcriptional regulation of Inositol Trisphosphate Receptor Type 1 (IP3R1) pre-mRNA at least in part by interacting with CHERP (Ca2+ homeostasis endoplasmic reticulum protein) calcium-dependently. ALG-2 contains five serially repeated EF-hand motifs and interacts with various proteins, including ALG-2-interacting protein X (Alix), Fas, annexin XI, death-associated protein kinase 1 (DAPk1), Tumor susceptibility gene 101 (TSG101), Sec31A, phospholipid scramblase 3 (PLSCR3), the P-body component PATL1, and endosomal sorting complex required for transport (ESCRT)-III-related protein IST1, in a calcium-dependent manner. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination.

Pssm-ID: 320058 [Multi-domain] Cd Length: 165 Bit Score: 59.58 E-value: 2.29e-11

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  58 LKAVFTNIDTDKSGTITYEELKTGLARlG--SRLSEAEVEQLMEAADVDGNGTIDYIEFVTatmhqhklerdehLYK--- 132
Cdd:cd16183     2 LWNVFQRVDKDRSGQISATELQQALSN-GtwTPFNPETVRLMIGMFDRDNSGTINFQEFAA-------------LWKyit 67

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183 133 ----AFQYFDKDHSGFITRDELETAMKEYG-----------------MG------DD--------ATIREIISEVDTDND 177
Cdd:cd16183    68 dwqnCFRSFDRDNSGNIDKNELKQALTSFGyrlsdqfydilvrkfdrQGrgtiafDDfiqccvvlQTLTDSFRRYDTDQD 147

                         170
                  ....*....|...
gi 2526894183 178 GRIN--YEEFCTM 188
Cdd:cd16183   148 GWIQisYEQFLEM 160

EF-hand, calcium binding motif, found in calumenin, reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins; The family corresponds to a group of six EF-hand Ca2+-binding proteins, including calumenin (also known as crocalbin or CBP-50), reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins. Calumenin is an endo/sarcoplasmic reticulum (ER/SR) resident low-affinity Ca2+-binding protein that contains six EF-hand domains and a C-terminal SR retention signal His-Asp-Glu-Phe (HDEF) tetrapeptide. It functions as a novel regulator of SERCA2, and its expressional changes are tightly coupled with Ca2+-cycling of cardiomyocytes. It is also broadly involved in haemostasis and in the pathophysiology of thrombosis. Moreover, the extracellular calumenin acts as a suppressor of cell migration and tumor metastasis. RCN-1 is an endoplasmic reticulum resident Ca2+-binding protein with a carboxyl-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide signal. It acts as a potential negative regulator of B-RAF activation and can negatively modulate cardiomyocyte hypertrophy by inhibition of the mitogen-activated protein kinase signalling cascade. It also plays a key role in the development of doxorubicin-associated resistance. RCN-3 is a putative six EF-hand Ca2+-binding protein that contains five RXXR (X is any amino acid) motifs and a C-terminal ER retrieval signal HDEL tetrapeptide. The RXXR motif represents the target sequence of subtilisin-like proprotein convertases (SPCs). RCN-3 is specifically bound to the paired basic amino-acid-cleaving enzyme-4 (PACE4) precursor protein and plays an important role in the biosynthesis of PACE4.

Pssm-ID: 320024 [Multi-domain] Cd Length: 264 Bit Score: 58.36 E-value: 2.28e-10

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  49 NLSEEEIKG-LKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVTAT--------- 118
Cdd:cd16226    27 QLTPEESKErLGIIVDKIDKNGDGFVTEEELKDWIKYVQKKYIREDVDRQWKEYDPNKDGKLSWEEYKKATygflddeee 106

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2526894183 119 ------MHQHKLERDEHLYKAFqyfDKDHSGFITRDELETAM--KEYGMGDDATIREIISEVDTDNDGRINYEEF 185
Cdd:cd16226   107 dddlheSYKKMIRRDERRWKAA---DQDGDGKLTKEEFTAFLhpEEFPHMRDIVVQETLEDIDKNKDGFISLEEY 178

EF-hand, calcium binding motif, found in uncharacterized calglandulin-like proteins; The family corresponds to a group of uncharacterized calglandulin-like proteins. Although their biological function remain unclear, they show high sequence similarity with human calglandulin-like protein GAGLP, which is an ortholog of calglandulin from the venom glands of Bothrops insularis snake. Both GAGLP and calglandulin are putative Ca2+-binding proteins with four EF-hand motifs. However, members in this family contain only three EF-hand motifs. In this point, they may belong to the parvalbumin-like EF-hand family, which is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix).

Pssm-ID: 319995 [Multi-domain] Cd Length: 106 Bit Score: 53.30 E-value: 1.27e-09

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183 101 ADVDGNGTIDYIEFVTATMH-QHKLERDEHLYKAFQYFDKDHSGFITRDELE-------TAMKEYGMGDDATiREIISEV 172
Cdd:cd16252     9 SEMRHHGSFNYSKFFEYMQKfQTSEQQEEAIRKAFQMLDKDKSGFIEWNEIKyilstvpSSMPVAPLSDEEA-EAMIQAA 87

                          90
                  ....*....|....*....
gi 2526894183 173 DTDNDGRINYEEFCTMMRS 191
Cdd:cd16252    88 DTDGDGRIDFQEFSDMVKK 106

EF-hand, calcium binding motif, found in parvalbumin-like EF-hand family; The family includes alpha- and beta-parvalbumins, and a group of uncharacterized calglandulin-like proteins. Parvalbumins are small, acidic, cytosolic EF-hand-containing Ca2+-buffer and Ca2+ transporter/shuttle proteins belonging to EF-hand superfamily. They are expressed by vertebrates in fast-twitch muscle cells, specific neurons of the central and peripheral nervous system, sensory cells of the mammalian auditory organ (Corti's cell), and some other cells, and characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Thus, they may play an additional role in Mg2+ handling. Moreover, parvalbumins represent one of the major animal allergens. In metal-bound states, parvalbumins possess a rigid and stable tertiary structure and display strong allergenicity. In contrast, the metal-free parvalbumins are intrinsically disordered, and the loss of metal ions results in a conformational change that decreases their IgE binding capacity. Furthermore, parvalbumins have been widely used as a neuronal marker for a variety of functional brain systems. They also function as a Ca2+ shuttle transporting Ca2+ from troponin-C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus they may facilitate myocardial relaxation and play important roles in cardiac diastolic dysfunction. Parvalbumins consists of alpha- and beta- sublineages, which can be distinguished on the basis of isoelectric point (pI > 5 for alpha; pI

Pssm-ID: 319994 [Multi-domain] Cd Length: 101 Bit Score: 53.31 E-value: 1.42e-09

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183 101 ADVDGNGTIDYIEFVTatMHQHKLERDEHLYKAFQYFDKDHSGFITRDELETAMKEYGMG----DDATIREIISEVDTDN 176
Cdd:cd16251     9 SAFRAHGSFNYKKFFE--HVGLKQKSEDQIKKVFQILDKDKSGFIEEEELKYILKGFSIAgrdlTDEETKALLAAGDTDG 86

                          90
                  ....*....|..
gi 2526894183 177 DGRINYEEFCTM 188
Cdd:cd16251    87 DGKIGVEEFATL 98

Penta-EF hand, calcium binding motifs, found in Group I PEF proteins; The family corresponds to Group I PEF proteins that have been found not only in higher animals but also in lower animals, plants, fungi and protists. Group I PEF proteins include apoptosis-linked gene 2 protein (ALG-2), peflin and similar proteins. ALG-2, also termed programmed cell death protein 6 (PDCD6), is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination. Peflin is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+.

Pssm-ID: 320055 [Multi-domain] Cd Length: 164 Bit Score: 52.92 E-value: 6.66e-09

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  53 EEIKGLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVTA--TMHqhklerdeHL 130
Cdd:cd16180    64 KYIQDWRRLFRRFDRDRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDFVEAcvTLK--------RL 135

                          90
                  ....*....|....*.
gi 2526894183 131 YKAFQYFDKDHSGFIT 146
Cdd:cd16180   136 TDAFRKYDTNRTGYAT 151

EF-hand, calcium binding motif, found in parvalbumin-like EF-hand family; The family includes alpha- and beta-parvalbumins, and a group of uncharacterized calglandulin-like proteins. Parvalbumins are small, acidic, cytosolic EF-hand-containing Ca2+-buffer and Ca2+ transporter/shuttle proteins belonging to EF-hand superfamily. They are expressed by vertebrates in fast-twitch muscle cells, specific neurons of the central and peripheral nervous system, sensory cells of the mammalian auditory organ (Corti's cell), and some other cells, and characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Thus, they may play an additional role in Mg2+ handling. Moreover, parvalbumins represent one of the major animal allergens. In metal-bound states, parvalbumins possess a rigid and stable tertiary structure and display strong allergenicity. In contrast, the metal-free parvalbumins are intrinsically disordered, and the loss of metal ions results in a conformational change that decreases their IgE binding capacity. Furthermore, parvalbumins have been widely used as a neuronal marker for a variety of functional brain systems. They also function as a Ca2+ shuttle transporting Ca2+ from troponin-C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus they may facilitate myocardial relaxation and play important roles in cardiac diastolic dysfunction. Parvalbumins consists of alpha- and beta- sublineages, which can be distinguished on the basis of isoelectric point (pI > 5 for alpha; pI

Pssm-ID: 319994 [Multi-domain] Cd Length: 101 Bit Score: 51.38 E-value: 6.67e-09

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2526894183  58 LKAVFTNIDTDKSGTITYEELK---TGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVT 116
Cdd:cd16251    36 IKKVFQILDKDKSGFIEEEELKyilKGFSIAGRDLTDEETKALLAAGDTDGDGKIGVEEFAT 97

EF-hand domain pair;

Pssm-ID: 463900 [Multi-domain] Cd Length: 67 Bit Score: 50.33 E-value: 7.33e-09

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2526894183  58 LKAVFTNIDTDKSGTITYEELKTGLARLGSR--LSEAEVEQLMEAADVDGNGTIDYIEFVTATM 119
Cdd:pfam13499   4 LKEAFKLLDSDGDGYLDVEELKKLLRKLEEGepLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

EF-hand domain pair;

Pssm-ID: 404678 [Multi-domain] Cd Length: 54 Bit Score: 49.24 E-value: 1.25e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2526894183 141 HSGFITRDELETAMKEYGMGD--DATIREIISEVDTDNDGRINYEEFCTMM 189
Cdd:pfam13833   1 EKGVITREELKRALALLGLKDlsEDEVDILFREFDTDGDGYISFDEFCVLL 51

calmodulin; Provisional

Pssm-ID: 185504 [Multi-domain] Cd Length: 149 Bit Score: 51.69 E-value: 1.47e-08

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2526894183 132 KAFQYFDKDHSGFITRDELETAMKEYGMG-DDATIREIISEVDTDNDGRINYEEFCTMMRSGMQQQ 196
Cdd:PTZ00184   15 EAFSLFDKDGDGTITTKELGTVMRSLGQNpTEAELQDMINEVDADGNGTIDFPEFLTLMARKMKDT 80

centrin; Provisional

Pssm-ID: 185503 [Multi-domain] Cd Length: 158 Bit Score: 51.61 E-value: 1.48e-08

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183 125 ERDEHLYKAFQYFDKDHSGFITRDELETAMKEYGMG-DDATIREIISEVDTDNDGRINYEEFCTMM---------RSGMQ 194
Cdd:PTZ00183   14 DQKKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEpKKEEIKQMIADVDKDGSGKIDFEEFLDIMtkklgerdpREEIL 93


                  ....*.
gi 2526894183 195 QQGKLF 200
Cdd:PTZ00183   94 KAFRLF 99

Ca2+-binding protein, EF-hand superfamily [Signal transduction mechanisms];

Pssm-ID: 444056 [Multi-domain] Cd Length: 137 Bit Score: 50.95 E-value: 2.21e-08

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2526894183 125 ERDEHLYKAFQYFDKDHSGFITRDELETAMkeygmgdDATIREIISEVDTDNDGRINYEEFCTMMRSGMQQ 195
Cdd:COG5126     2 LQRRKLDRRFDLLDADGDGVLERDDFEALF-------RRLWATLFSEADTDGDGRISREEFVAGMESLFEA 65

The penta-EF hand (PEF) family; The penta-EF hand (PEF) family contains a group of five EF-hand calcium-binding proteins, including several classical calpain large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14), two calpain small subunits (CAPNS1 and CAPNS2), as well as non-calpain PEF proteins, ALG-2 (apoptosis-linked gene 2, also termed programmed cell death protein 6, PDCD6), peflin, sorcin, and grancalcin. Based on the sequence similarity of EF1 hand, ALG-2 and peflin have been classified into group I PEF proteins. Calcium-dependent protease calpain subfamily members, sorcin and grancalcin, are group II PEF proteins. Calpains (EC 3.4.22.17) are calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates. They have been implicated in a number of physiological processes such as cell cycle progression, remodeling of cytoskeletal-cell membrane attachments, signal transduction, gene expression and apoptosis. ALG-2 is a pro-apoptotic factor that forms a homodimer in the cell or a heterodimer with its closest paralog peflin through their EF5s. Peflin is a 30-kD PEF protein with a longer N-terminal hydrophobic domain than any other member of the PEF family, and it contains nine nonapeptide (A/PPGGPYGGP) repeats. It exists only as a heterodimer with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. ALG-2 interacts with various proteins in a Ca2+-dependent manner. Sorcin (for soluble resistance-related calcium binding protein) is a soluble resistance-related calcium-binding protein that participates in the regulation of calcium homeostasis in cells. Grancalcin is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It plays a key role in leukocyte-specific functions that are responsible for host defense. Grancalcin can form a heterodimer together with sorcin. Members in this family contain five EF-hand motifs attached to an N-terminal region of variable length containing one or more short Gly/Pro-rich sequences. These proteins form homodimers or heterodimers through pairing between the 5th EF-hands from the two molecules. Unlike calmodulin, the PEF domains do not undergo major conformational changes upon binding Ca2+.

Pssm-ID: 320054 [Multi-domain] Cd Length: 165 Bit Score: 51.28 E-value: 2.38e-08

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  55 IKGLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADvDGNGTIDYIEFVTATMhqhKLERdehLYKAF 134
Cdd:cd15897    69 IKAWQEIFRTYDTDGSGTIDSNELRQALSGAGYRLSEQTYDIIIRRYD-RGRGNIDFDDFIQCCV---RLQR---LTDAF 141

                          90
                  ....*....|..
gi 2526894183 135 QYFDKDHSGFIT 146
Cdd:cd15897   142 RRYDKDQDGQIQ 153

EF-hand, calcium binding motif, found in beta-parvalbumin; Beta-parvalbumin, also termed Oncomodulin-1 (OM), is a small calcium-binding protein that is expressed in hepatomas, as well as in the blastocyst and the cytotrophoblasts of the placenta. It is also found to be expressed in the cochlear outer hair cells of the organ of Corti and frequently expressed in neoplasms. Mammalian beta-parvalbumin is secreted by activated macrophages and neutrophils. It may function as a tissue-specific Ca2+-dependent regulatory protein, and may also serve as a specialized cytosolic Ca2+ buffer. Beta-parvalbumin acts as a potent growth-promoting signal between the innate immune system and neurons in vivo. It has high and specific affinity for its receptor on retinal ganglion cells (RGC) and functions as the principal mediator of optic nerve regeneration. It exerts its effects in a cyclic adenosine monophosphate (cAMP)-dependent manner and can further elevate intracellular cAMP levels. Moreover, beta-parvalbumin is associated with efferent function and outer hair cell electromotility, and can identify different hair cell types in the mammalian inner ear. Beta-parvalbumin is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. The EF site displays a high-affinity for Ca2+/Mg2+, and the CD site is a low-affinity Ca2+-specific site. In addition, beta-parvalbumin is distinguished from other parvalbumins by its unusually low isoelectric point (pI = 3.1) and sequence eccentricities (e.g., Y57-L58-D59 instead of F57-I58-E59).

Pssm-ID: 319998 [Multi-domain] Cd Length: 101 Bit Score: 49.73 E-value: 2.60e-08

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  50 LSEEEIKGLKAVFTNIDTDKSGTITYEELKTGLARLGSR---LSEAEVEQLMEAADVDGNGTIDYIEFVT 116
Cdd:cd16255    28 LSKKSADDVKKVFEIIDQDKSGFIEEEELKLFLQNFSSGareLTDAETKAFLKAGDSDGDGKIGVEEFQA 97

EF-hand, calcium binding motif, found in homologs of mammalian apoptosis-linked gene 2 protein (ALG-2); The family includes some homologs of mammalian apoptosis-linked gene 2 protein (ALG-2) mainly found in lower eukaryotes, such as a parasitic protist Leishmarua major and a cellular slime mold Dictyostelium discoideum. These homologs contains five EF-hand motifs. Due to the presence of unfavorable residues at the Ca2+-coordinating positions, their non-canonical EF4 and EF5 hands may not bind Ca2+. Two Dictyostelium PEF proteins are the prototypes of this family. They may bind to cytoskeletal proteins and/or signal-transducing proteins localized to detergent-resistant membranes named lipid rafts, and occur as monomers or weak homo- or heterodimers like ALG-2. They can serve as a mediator for Ca2+ signaling-related Dictyostehum programmed cell death (PCD).

Pssm-ID: 320060 [Multi-domain] Cd Length: 163 Bit Score: 51.06 E-value: 2.66e-08

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  58 LKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTI---DYIEFvTATMHQHKlerdehlyKAF 134
Cdd:cd16185    68 MQNGFEQRDTSRSGRLDANEVHEALAASGFQLDPPAFQALFRKFDPDRGGSLgfdDYIEL-CIFLASAR--------NLF 138

                          90
                  ....*....|....
gi 2526894183 135 QYFDKDHSGFITRD 148
Cdd:cd16185   139 QAFDRQRTGRVTLD 152

EF-hand, calcium binding motif, found in CREC-EF hand family; The CREC (Cab45/reticulocalbin/ERC45/calumenin)-EF hand family contains a group of six EF-hand, low-affinity Ca2+-binding proteins, including reticulocalbin (RCN-1), ER Ca2+-binding protein of 55 kDa (ERC-55, also known as TCBP-49 or E6BP), reticulocalbin-3 (RCN-3), Ca2+-binding protein of 45 kDa (Cab45 and its splice variant Cab45b), and calumenin ( also known as crocalbin or CBP-50). The proteins are not only localized in various parts of the secretory pathway, but also found in the cytosolic compartment and at the cell surface. They interact with different ligands or proteins and have been implicated in the secretory process, chaperone activity, signal transduction as well as in a large variety of disease processes.

Pssm-ID: 320021 [Multi-domain] Cd Length: 267 Bit Score: 52.06 E-value: 3.03e-08

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  52 EEEIKGLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVTATM------------ 119
Cdd:cd15899    31 EESKRRLGVIVSKMDVDKDGFISAKELHSWILESFKRHAMEESKEQFRAVDPDEDGHVSWDEYKNDTYgsvgddeenvad 110

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183 120 -------HQHKLERDEhlyKAFQYFDKDHSGFITRDELeTAMK---EYGMGDDATIREIISEVDTDNDGRINYEEFCTMM 189
Cdd:cd15899   111 nikedeeYKKLLLKDK---KRFEAADQDGDLILTLEEF-LAFLhpeESPYMLDFVIKETLEDLDKNGDGFISLEEFISDP 186


                  ..
gi 2526894183 190 RS 191
Cdd:cd15899   187 YS 188

Penta-EF hand, calcium binding motifs, found in Group I PEF proteins; The family corresponds to Group I PEF proteins that have been found not only in higher animals but also in lower animals, plants, fungi and protists. Group I PEF proteins include apoptosis-linked gene 2 protein (ALG-2), peflin and similar proteins. ALG-2, also termed programmed cell death protein 6 (PDCD6), is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination. Peflin is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+.

Pssm-ID: 320055 [Multi-domain] Cd Length: 164 Bit Score: 50.99 E-value: 3.23e-08

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 2526894183 130 LYKAFQYFDKDHSGFITRDELETAMKEYGM--GDDATIREIISEVDTDNDGRINYEEFC 186
Cdd:cd16180     2 LRRIFQAVDRDRSGRISAKELQRALSNGDWtpFSIETVRLMINMFDRDRSGTINFDEFV 60

EF-hand, calcium binding motif, found in uncharacterized calglandulin-like proteins; The family corresponds to a group of uncharacterized calglandulin-like proteins. Although their biological function remain unclear, they show high sequence similarity with human calglandulin-like protein GAGLP, which is an ortholog of calglandulin from the venom glands of Bothrops insularis snake. Both GAGLP and calglandulin are putative Ca2+-binding proteins with four EF-hand motifs. However, members in this family contain only three EF-hand motifs. In this point, they may belong to the parvalbumin-like EF-hand family, which is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix).

Pssm-ID: 319995 [Multi-domain] Cd Length: 106 Bit Score: 49.45 E-value: 3.57e-08

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2526894183  51 SEEEIKGLKAVFTNIDTDKSGTITYEELKTGLARLGSR-----LSEAEVEQLMEAADVDGNGTIDYIEF 114
Cdd:cd16252    32 SEQQEEAIRKAFQMLDKDKSGFIEWNEIKYILSTVPSSmpvapLSDEEAEAMIQAADTDGDGRIDFQEF 100

EF-hand, calcium binding motif, found in the hexa-EF hand proteins family; The hexa-EF hand proteins family, also named the calbindin sub-family, contains a group of six EF-hand Ca2+-binding proteins, including calretinin (CR, also termed 29 kDa calbindin), calbindin D28K (CB, also termed vitamin D-dependent calcium-binding protein, avian-type), and secretagogin (SCGN). CR is a cytosolic hexa-EF-hand calcium-binding protein predominantly expressed in a variety of normal and tumorigenic t-specific neurons of the central and peripheral nervous system. It is a multifunctional protein implicated in many biological processes, including cell proliferation, differentiation, and cell death. CB is highly expressed in brain tissue. It is a strong calcium-binding and buffering protein responsible for preventing a neuronal death as well as maintaining and controlling calcium homeostasis. SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a Ca2+ sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. Although the family members share a significant amount of secondary sequence homology, they display altered structural and biochemical characteristics, and operate in distinct fashions. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. They harbor two and four EF-hand motifs, respectively. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. Human SCGN simultaneously binds four calcium ions through its EF-hands 3, 4, 5 and 6 in one high affinity and three low affinity calcium-binding sites. In contrast, SCGNs in other lower eukaryotes, such as D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, are fully competent in terms of six calcium-binding.

Pssm-ID: 320075 [Multi-domain] Cd Length: 254 Bit Score: 51.20 E-value: 6.50e-08

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  61 VFTNIDTDKSGTITYEELKTGL-----ARLGSRLSEAEVEQ----LMEAADVDGNGTIDYIE----------FVTATMHQ 121
Cdd:cd15902     4 VWMHFDADGNGYIEGKELDSFLrellkALNGKDKTDDEVAEkkkeFMEKYDENEDGKIEIRElanilpteenFLLLFRRE 83

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2526894183 122 HKLERDEHLYKAFQYFDKDHSGFITRDELETAMKE------YGMGDDAT---IREIISEVDTDNDGRINYEEF 185
Cdd:cd15902    84 QPLISSVEFMKIWRKYDTDGSGFIEAKELKGFLKDlllknkKHVSPPKLdeyTKLILKEFDANKDGKLELDEM 156

Penta-EF hand, calcium binding motifs, found in mu-type calpain (CAPN1), m-type calpain (CAPN2), and similar proteins; The family includes mu-type calpain (CAPN1) and m-type calpain (CAPN2), both of which are ubiquitously expressed 80-kDa Ca2+-dependent intracellular cysteine proteases that contain a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain. The catalytic subunit CAPN1 or CAPN2 in complex with a regulatory subunit encoded by CAPNS1 forms a mu- or m-calpain heterodimer, respectively.

Pssm-ID: 320064 [Multi-domain] Cd Length: 168 Bit Score: 48.89 E-value: 1.91e-07

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  55 IKGLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAeVEQLMEAADVDGNGTIDYIEFVTAtmhqhkLERDEHLYKAF 134
Cdd:cd16189    72 IQKYLKIYKKFDTDGSGTMSSYEMRLALEEAGFKLNNQ-LHQVLVARYADQELTIDFDNFVRC------LVRLELLFKIF 144

                          90
                  ....*....|....*..
gi 2526894183 135 QYFDKDHSGFITRDELE 151
Cdd:cd16189   145 KQLDKDNTGTIELDLIQ 161

EF-hand, calcium binding motif, found in reticulocalbin-2 (RCN2) mainly from protostomes; This family corresponds to a group of uncharacterized RCN2-like proteins, which are mainly found in protostomes. Although their biological function remains unclear, they show high sequence similarity with RCN2 (also known as E6BP or TCBP-49), which is an endoplasmic reticulum resident low-affinity Ca2+-binding protein that has been implicated in immunity, redox homeostasis, cell cycle regulation and coagulation. Members in this family contain six copies of the EF-hand Ca2+-binding motif, but may lack a C-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide that is required for retention of RCN2 in the endoplasmic reticulum (ER).

Pssm-ID: 320025 [Multi-domain] Cd Length: 263 Bit Score: 49.62 E-value: 2.02e-07

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  49 NLSEEEIKG-LKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVTAT--------- 118
Cdd:cd16227    28 ELPPEEAKRrLAVLAKKMDLNDDGFIDRKELKAWILRSFKMLDEEEANERFEEADEDGDGKVTWEEYLADSfgyddedne 107

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2526894183 119 -MHQHKLERDEHLY----KAFQYFDKDHSGFITRDELE--TAMKEYGMGDDATIREIISEVDTDNDGRINYEEF 185
Cdd:cd16227   108 eMIKDSTEDDLKLLeddkEMFEAADLNKDGKLDKTEFSafQHPEEYPHMHPVLIEQTLRDKDKDNDGFISFQEF 181

EF-hand, calcium binding motif, found in the hexa-EF hand proteins family; The hexa-EF hand proteins family, also named the calbindin sub-family, contains a group of six EF-hand Ca2+-binding proteins, including calretinin (CR, also termed 29 kDa calbindin), calbindin D28K (CB, also termed vitamin D-dependent calcium-binding protein, avian-type), and secretagogin (SCGN). CR is a cytosolic hexa-EF-hand calcium-binding protein predominantly expressed in a variety of normal and tumorigenic t-specific neurons of the central and peripheral nervous system. It is a multifunctional protein implicated in many biological processes, including cell proliferation, differentiation, and cell death. CB is highly expressed in brain tissue. It is a strong calcium-binding and buffering protein responsible for preventing a neuronal death as well as maintaining and controlling calcium homeostasis. SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a Ca2+ sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. Although the family members share a significant amount of secondary sequence homology, they display altered structural and biochemical characteristics, and operate in distinct fashions. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. They harbor two and four EF-hand motifs, respectively. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. Human SCGN simultaneously binds four calcium ions through its EF-hands 3, 4, 5 and 6 in one high affinity and three low affinity calcium-binding sites. In contrast, SCGNs in other lower eukaryotes, such as D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, are fully competent in terms of six calcium-binding.

Pssm-ID: 320075 [Multi-domain] Cd Length: 254 Bit Score: 49.66 E-value: 2.39e-07

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  29 MKQFRTMNKLKqlalkviaenLSEEEIKglkaVFTNIDTDKSGTITYEELKTGLARLGSRLS--------EAEVEQLMEA 100
Cdd:cd15902    77 LLLFRREQPLI----------SSVEFMK----IWRKYDTDGSGFIEAKELKGFLKDLLLKNKkhvsppklDEYTKLILKE 142

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183 101 ADVDGNGTIDYIEFVT------------ATMHQHKLERDEhLYKAFQYFDKDHSGFITRDELETAMKEYGMGDDATIRE- 167
Cdd:cd15902   143 FDANKDGKLELDEMAKllpvqenfllkfQILGAMDLTKED-FEKVFEHYDKDNNGVIEGNELDALLKDLLEKNKADIDKp 221

                         170       180       190
                  ....*....|....*....|....*....|...
gi 2526894183 168 --------IISEVDTDNDGRINYEEFCTMMRSG 192
Cdd:cd15902   222 dlenfrdaILRACDKNKDGKIQKTELALFLSAK 254

Calcium-activated neutral; CAPN3, also termed calcium-activated neutral proteinase 3 (CANP 3), or calpain L3, or calpain p94, or muscle-specific calcium-activated neutral protease 3, or new calpain 1 (nCL-1), is a calpain large subunit that is mainly expressed in skeletal muscle, or lens. The skeletal muscle-specific CAPN3 are pathologically associated with limb girdle muscular dystrophy type 2A (LGMD2A). Its autolytic activity can be positively regulated by calmodulin (CaM), a known transducer of the calcium signal. CAPN3 is also involved in human melanoma tumorigenesis and progression. It impairs cell proliferation and stimulates oxidative stress-mediated cell death in melanoma cells. Moreover, it plays an important role in sarcomere remodeling and mitochondrial protein turnover. Furthermore, the phosphorylated skeletal muscle-specific CAPN3 acts as a myofibril structural component and may participate in myofibril-based signaling pathways. In the eye, the lens-specific CAPN3, together with CAPN2, is responsible for proteolytic cleavages of alpha and beta-crystallin. Overactivated alpha and beta-crystallin can lead to cataract formation. CAPN3 exists as a homodimer, rather than a heterodimer with the calpain small subunit. It may also form heterodimers with other calpain large subunits. CAPN3 contains a long N-terminal region, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain. Ca2+ binding at EF5 of the CAPN3 PEF domain is a distinct feature not observed in other calpain isoforms.

Pssm-ID: 320065 [Multi-domain] Cd Length: 169 Bit Score: 47.93 E-value: 4.33e-07

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  53 EEIKGLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEaEVEQLMEAADVDGNGTIDYIEFVTAtmhqhkLERDEHLYK 132
Cdd:cd16190    70 NKIKQWQKIFKRYDTDKSGTINSYEMRNAVNDAGFRLNN-QLYDIITMRYADKHMNIDFDSFICC------FVRLEGMFR 142

                          90
                  ....*....|....*....
gi 2526894183 133 AFQYFDKDHSGFITRDELE 151
Cdd:cd16190   143 AFHAFDKDGDGIIKLNVLE 161

EF-hand, calcium binding motif, found in beta-parvalbumin; Beta-parvalbumin, also termed Oncomodulin-1 (OM), is a small calcium-binding protein that is expressed in hepatomas, as well as in the blastocyst and the cytotrophoblasts of the placenta. It is also found to be expressed in the cochlear outer hair cells of the organ of Corti and frequently expressed in neoplasms. Mammalian beta-parvalbumin is secreted by activated macrophages and neutrophils. It may function as a tissue-specific Ca2+-dependent regulatory protein, and may also serve as a specialized cytosolic Ca2+ buffer. Beta-parvalbumin acts as a potent growth-promoting signal between the innate immune system and neurons in vivo. It has high and specific affinity for its receptor on retinal ganglion cells (RGC) and functions as the principal mediator of optic nerve regeneration. It exerts its effects in a cyclic adenosine monophosphate (cAMP)-dependent manner and can further elevate intracellular cAMP levels. Moreover, beta-parvalbumin is associated with efferent function and outer hair cell electromotility, and can identify different hair cell types in the mammalian inner ear. Beta-parvalbumin is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. The EF site displays a high-affinity for Ca2+/Mg2+, and the CD site is a low-affinity Ca2+-specific site. In addition, beta-parvalbumin is distinguished from other parvalbumins by its unusually low isoelectric point (pI = 3.1) and sequence eccentricities (e.g., Y57-L58-D59 instead of F57-I58-E59).

Pssm-ID: 319998 [Multi-domain] Cd Length: 101 Bit Score: 45.88 E-value: 6.19e-07

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2526894183 132 KAFQYFDKDHSGFITRDELETAMKEYGMG----DDATIREIISEVDTDNDGRINYEEFCTMMRS 191
Cdd:cd16255    38 KVFEIIDQDKSGFIEEEELKLFLQNFSSGarelTDAETKAFLKAGDSDGDGKIGVEEFQALVKA 101

EF-hand, calcium binding motif, found in reticulocalbin-2 (RCN2); RCN2, also termed calcium-binding protein ERC-55, or E6-binding protein (E6BP), or TCBP-49, is an endoplasmic reticulum resident low-affinity Ca2+-binding protein that has been implicated in immunity, redox homeostasis, cell cycle regulation and coagulation. It is associated with tumorigenesis, in particular with transformation of cells of the cervix induced by human papillomavirus (HPV), through binding to human papillomavirus (HPV) E6 oncogenic protein. It specifically interacts with vitamin D receptor among nuclear receptors. RCN2 contains an N-terminal signal sequence followed by six copies of the EF-hand Ca2+-binding motif, and a C-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide that is required for retention of RCN2 in the endoplasmic reticulum (ER).

Pssm-ID: 320022 [Multi-domain] Cd Length: 268 Bit Score: 48.20 E-value: 6.81e-07

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  51 SEEEIKGLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFvTATMHQHKLERDE-- 128
Cdd:cd16224    31 PEEQQKRLKSIIKKIDTDSDGFLTEEELSSWIQQSFRHYALEDAKQQFPEYDKDGDGAVTWDEY-NMQMYDRVIDYDEdt 109

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183 129 -------------HL--YKAFQYFDKDHSG------FITRDELETA--MKEYgmgddaTIREIISEVDTDNDGRINYEEF 185
Cdd:cd16224   110 vlddeeeesfrqlHLkdKKRFDKANTDGGPglnlteFIAFEHPEEVdyMTEF------VIQEALEEHDKDGDGFISLEEF 183

Eps15 homology domain; found in proteins implicated in endocytosis, vesicle transport, and signal transduction. The alignment contains a pair of EF-hand motifs, typically one of them is canonical and binds to Ca2+, while the other may not bind to Ca2+. A hydrophobic binding pocket is formed by residues from both EF-hand motifs. The EH domain binds to proteins containing NPF (class I), [WF]W or SWG (class II), or H[TS]F (class III) sequence motifs.

Pssm-ID: 238009 [Multi-domain] Cd Length: 67 Bit Score: 44.52 E-value: 1.20e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 2526894183 132 KAFQYFDKDHSGFITRDELETAMKEYGMgDDATIREIISEVDTDNDGRINYEEFCTMMR 190
Cdd:cd00052     3 QIFRSLDPDGDGLISGDEARPFLGKSGL-PRSVLAQIWDLADTDKDGKLDKEEFAIAMH 60

Eps15 homology domain; Pair of EF hand motifs that recognise proteins containing Asn-Pro-Phe (NPF) sequences.

Pssm-ID: 197477 [Multi-domain] Cd Length: 96 Bit Score: 44.19 E-value: 2.28e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 2526894183  134 FQYFDKDHSGFITRDELETAMKEYGMgDDATIREIISEVDTDNDGRINYEEFCTMMR 190
Cdd:smart00027  16 FRSLDKNQDGTVTGAQAKPILLKSGL-PQTLLAKIWNLADIDNDGELDKDEFALAMH 71

EF-hand, calcium binding motif, found in alpha-parvalbumin; Alpha-parvalbumin is cytosolic Ca2+/Mg2+-binding protein expressed mainly in fast-twitch skeletal myofibrils, where it may act as a soluble relaxing factor facilitating the Ca2+-mediated relaxation phase. It is also expressed in rapidly firing neurons, particularly GABA-ergic neurons, and thus may confer protection against Ca2+ toxicity. The major role of alpha-parvalbumin is metal buffering and transport of Ca2+. It binds different metal cations, and exhibits very high affinity for Ca2+ and physiologically significant affinity for Mg2+. Alpha-parvalbumin is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Both metal ion-binding sites in alpha-parvalbumin are high-affinity sites. Additionally, in contrast to beta-parvalbumin, alpha-parvalbumin is less acidic and has an additional residue in the C-terminal helix.

Pssm-ID: 319997 [Multi-domain] Cd Length: 101 Bit Score: 44.43 E-value: 2.35e-06

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2526894183  58 LKAVFTNIDTDKSGTITYEELK---TGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVT 116
Cdd:cd16254    36 VKKVFHILDKDKSGFIEEDELKfvlKGFSPDGRDLSDKETKALLAAGDKDGDGKIGIDEFAT 97

Penta-EF hand, calcium binding motifs, found in calpain-13 (CAPN13), calpain-14 (CAPN14), and similar proteins; CAPN13, also termed calcium-activated neutral proteinase 13 (CANP 13), a 63.6 kDa calpain large subunit that exhibits a restricted tissue distribution with low levels of expression detected only in human testis and lung. In calpain family, CAPN13 is most closely related to calpain-14 (CAPN14). CAPN14, also termed calcium-activated neutral proteinase 14 (CANP 14), is a 76.7 kDa calpain large subunit that is most highly expressed in the oesophagus. Its expression and calpain activity can be induced by IL-13. Both CAPN13 and CAPN14 contain a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain.

Pssm-ID: 320070 [Multi-domain] Cd Length: 168 Bit Score: 45.27 E-value: 3.55e-06

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  76 EELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVTatmhqhkLERDEHLYKA-FQYFDKDHSGFITRDELETAM 154
Cdd:cd16195    27 ENLLKGLAGSGGGFSLDACRSMVALMDLSVNGRLSLEEFSR-------LWKKLRKYKDiFQKADVSKSGFLSLSELRNAI 99

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 2526894183 155 KEYGMGDDATIREIISEVDTDNDGRINYEEF-CTMMR 190
Cdd:cd16195   100 QAAGIRVSDDLLNLMALRYGDSSGRISFESFiCLMLR 136

EF-hand, calcium binding motif; EF-hands are calcium-binding motifs that occur at least in pairs. Links between disease states and genes encoding EF-hands, particularly the S100 subclass, are emerging. Each motif consists of a 12 residue loop flanked on either side by a 12 residue alpha-helix. EF-hands undergo a conformational change unpon binding calcium ions.

Pssm-ID: 197492 [Multi-domain] Cd Length: 29 Bit Score: 41.98 E-value: 4.25e-06

                           10        20
                   ....*....|....*....|....*..
gi 2526894183  165 IREIISEVDTDNDGRINYEEFCTMMRS 191
Cdd:smart00054   2 LKEAFRLFDKDGDGKIDFEEFKDLLKA 28

EF-hand, calcium binding motif, found in peflin and similar proteins; Peflin, also termed penta-EF hand (PEF) protein with a long N-terminal hydrophobic domain, or penta-EF hand domain-containing protein 1, is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. In lower vertebrates, peflin may interact with transient receptor potential N (TRPN1), suggesting a potential role of peflin in fast transducer channel adaptation.

Pssm-ID: 320059 [Multi-domain] Cd Length: 165 Bit Score: 44.95 E-value: 4.32e-06

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  59 KAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEF-VTATMHQhklerdeHLYKAFQYF 137
Cdd:cd16184    70 KQVFQQFDRDRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRARRSLTLDQFiQVCVQLQ-------SLTDAFRQR 142


                  ....*....
gi 2526894183 138 DKDHSGFIT 146
Cdd:cd16184   143 DTQMTGTIT 151

EF-hand, calcium binding motif, found in parvalbumins; Parvalbumins are small, acidic, cytosolic EF-hand-containing Ca2+-buffer and Ca2+ transporter/shuttle proteins belonging to EF-hand superfamily. They are expressed by vertebrates in fast-twitch muscle cells, specific neurons of the central and peripheral nervous system, sensory cells of the mammalian auditory organ (Corti's cell), and some other cells, and characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Thus, they may play an additional role in Mg2+ handling. Moreover, parvalbumins represent one of the major animal allergens. In metal-bound states, parvalbumins possess a rigid and stable tertiary structure and display strong allergenicity. In contrast, the metal-free parvalbumins are intrinsically disordered, and the loss of metal ions results in a conformational change that decreases their IgE binding capacity. Furthermore, parvalbumins have been widely used as a neuronal marker for a variety of functional brain systems. They also function as a Ca2+ shuttle transporting Ca2+ from troponin-C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus they may facilitate myocardial relaxation and play important roles in cardiac diastolic dysfunction. Parvalbumins consists of alpha- and beta- sublineages, which can be distinguished on the basis of isoelectric point (pI > 5 for alpha; pI

Pssm-ID: 319996 [Multi-domain] Cd Length: 101 Bit Score: 43.32 E-value: 5.36e-06

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183 107 GTIDYIEFVTATMHQHKleRDEHLYKAFQYFDKDHSGFITRDELETAMKEYGMG----DDATIREIISEVDTDNDGRINY 182
Cdd:cd16253    15 DSFDHKAFFKAVGLSKK--SPADIKKVFNILDQDKSGFIEEEELKLFLKNFSDGarvlSDKETKNFLAAGDSDGDGKIGV 92


                  ....*...
gi 2526894183 183 EEFCTMMR 190
Cdd:cd16253    93 DEFKSMVK 100

EF-hand, calcium binding motif, found in calumenin; Calumenin, also termed crocalbin, or IEF SSP 9302, is an endo/sarcoplasmic reticulum (ER/SR) resident low-affinity Ca2+-binding protein that contains six EF-hand domains and a C-terminal SR retention signal His-Asp-Glu-Phe (HDEF) tetrapeptide. It is highly expressed in various brain regions. Thus it plays an important role in migration and differentiation of neurons, and/or in Ca2+ signaling between glial cells and neurons. Calumenin is involved in Ca2+ homeostasis through interacting with ryanodine receptor RyR2 and SERCA2. It acts as a novel regulator of SERCA2, and its expressional changes are tightly coupled with Ca2+-cycling of cardiomyocytes. Calumenin also forms a Ca2+-dependent complex with thrombospondin-1, which is broadly involved in haemostasis and thrombosis. Moreover, calumenin is a molecular chaperone that endogenously regulates the vitamin K-dependent gamma-carboxylation of several proteins, including blood coagulation factors (such as FII, FVII, FIX, FX, and proteins C, S and Z), cell survival factors (Gas6) and bone metabolism proteins (such as matrix Gla protein or MGP, osteocalcin and periostin), through targeting the gamma-glutamyl carboxylase. It also functions as a charged F508del-cystic fibrosis transmembrane regulator (CFTR) folding modulator, as well as a G551D-CFTR associated protein. Furthermore, the extracellular calumenin acts as a suppressor of cell migration and tumor metastasis. It binds to and stabilizes fibulin-1, and further inactivates extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling.

Pssm-ID: 320026 [Multi-domain] Cd Length: 263 Bit Score: 45.70 E-value: 5.74e-06

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  52 EEEIKGLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVTATM------------ 119
Cdd:cd16228    31 EESKERLGKIVGKIDEDKDGFVTEDELKAWIKFAQKRWIYEDVERQWKGHDLNEDGLVSWEEYKNATYgyilddpdpddg 110

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2526894183 120 --HQHKLERDEhlyKAFQYFDKDHSGFITRDELETAM--KEYGMGDDATIREIISEVDTDNDGRINYEEFCTMMRS 191
Cdd:cd16228   111 fnYKQMMVRDE---RRFKMADKDGDLRATKEEFTAFLhpEEYDYMKDIVVLETMEDIDKNGDGFIDLEEYIGDMYS 183

Penta-EF hand, calcium binding motifs, found in PEF calpain family; The PEF calpain family belongs to the second group of penta-EF hand (PEF) proteins. It includes classical (also called conventional or typical) calpain (referring to a calcium-dependent papain-like enzymes, EC 3.4.22.17) large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14) and two calpain small subunits (CAPNS1 and CAPNS2), which are largely confined to animals (metazoans). These PEF-containing are nonlysosomal intracellular calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates in response to calcium signalling. The classical mu- and m-calpains are heterodimers consisting of homologous but a distinct (large) L-subunit/chain (CAPN1 or CAPN2) and a common (small) S-subunit/chain (CAPNS1 or CAPNS2). These L-subunits (CAPN1 and CAPN2) and S-subunit CAPNS1 are ubiquitously found in all tissues. Other calpains likely consist of an isolated L-subunit/chain alone. Many of them, such as CAPNS2, CAPN3 (in skeletal muscle, or lens), CAPN8 (in stomach), CAPN9 (in digestive tracts), CAPN11 (in testis), CAPN12 (in follicles), are tissue-specific and have specific functions in distinct organs. The L-subunits of similar structure (called CALPA and B) also have been found in Drosophila melanogaster. The S-subunit seems to have a chaperone-like function for proper folding of the L-subunit. The catalytic L-subunits contain a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain. The S-subunits only have the PEF domain following an N-terminal Gly-rich hydrophobic domain. The calpains undergo a rearrangement of the protein backbone upon Ca2+-binding.

Pssm-ID: 320057 [Multi-domain] Cd Length: 167 Bit Score: 44.52 E-value: 6.68e-06

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  54 EIKGLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAAdVDGNGTIDYIEFVTATMHQHKlerdehLYKA 133
Cdd:cd16182    70 DLKKWQAIFKKFDTDRSGTLSSYELRKALESAGFHLSNKVLQALVLRY-ADSTGRITFEDFVSCLVRLKT------AFET 142

                          90
                  ....*....|....*...
gi 2526894183 134 FQYFDKDHSGFITRDELE 151
Cdd:cd16182   143 FSALDKKNEGVIPLTLEE 160

EF hand; The EF-hands can be divided into two classes: signalling proteins and buffering/transport proteins. The first group is the largest and includes the most well-known members of the family such as calmodulin, troponin C and S100B. These proteins typically undergo a calcium-dependent conformational change which opens a target binding site. The latter group is represented by calbindin D9k and do not undergo calcium dependent conformational changes.

Pssm-ID: 425435 [Multi-domain] Cd Length: 29 Bit Score: 41.23 E-value: 7.01e-06

                          10        20
                  ....*....|....*....|....*..
gi 2526894183 165 IREIISEVDTDNDGRINYEEFCTMMRS 191
Cdd:pfam00036   2 LKEIFRLFDKDGDGKIDFEEFKELLKK 28

EF-hand, calcium binding motif, found in parvalbumins; Parvalbumins are small, acidic, cytosolic EF-hand-containing Ca2+-buffer and Ca2+ transporter/shuttle proteins belonging to EF-hand superfamily. They are expressed by vertebrates in fast-twitch muscle cells, specific neurons of the central and peripheral nervous system, sensory cells of the mammalian auditory organ (Corti's cell), and some other cells, and characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Thus, they may play an additional role in Mg2+ handling. Moreover, parvalbumins represent one of the major animal allergens. In metal-bound states, parvalbumins possess a rigid and stable tertiary structure and display strong allergenicity. In contrast, the metal-free parvalbumins are intrinsically disordered, and the loss of metal ions results in a conformational change that decreases their IgE binding capacity. Furthermore, parvalbumins have been widely used as a neuronal marker for a variety of functional brain systems. They also function as a Ca2+ shuttle transporting Ca2+ from troponin-C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus they may facilitate myocardial relaxation and play important roles in cardiac diastolic dysfunction. Parvalbumins consists of alpha- and beta- sublineages, which can be distinguished on the basis of isoelectric point (pI > 5 for alpha; pI

Pssm-ID: 319996 [Multi-domain] Cd Length: 101 Bit Score: 42.93 E-value: 8.78e-06

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 2526894183  50 LSEEEIKGLKAVFTNIDTDKSGTITYEELKTGLARL--GSR-LSEAEVEQLMEAADVDGNGTIDYIEF 114
Cdd:cd16253    28 LSKKSPADIKKVFNILDQDKSGFIEEEELKLFLKNFsdGARvLSDKETKNFLAAGDSDGDGKIGVDEF 95

Penta-EF hand, calcium binding motifs, found in calpain-8 (CAPN8); CAPN8, also termed new calpain 2 (nCL-2), or stomach-specific M-type calpain, is a calpain large subunit predominantly expressed in the stomach. It appears to be involved in membrane trafficking in the gastric surface mucus cells (pit cells), via its location at the Golgi and interaction with the beta-subunit of coatomer complex (beta-COP) of vesicles derived from the Golgi. Moreover, CAPN8, together with CAPN9, forms an active protease complex, G-calpain, in which both proteins are essential for stability and activity. The G-Calpain has been implicated in gastric mucosal defense. CAPN8 exists as both a monomer and homo-oligomer, but not as a heterodimer with the conventional calpain regulatory subunit (30K). The monomer and homodimer forms predominate. CAPN8 contains a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain.

Pssm-ID: 320066 [Multi-domain] Cd Length: 168 Bit Score: 43.62 E-value: 1.19e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  58 LKAVFTNIDTDKSgTITYEELKTGLARLGSR--------LSEAEVEQLMEAADVDGNGTIDYIEFVTATMhqhKLERDEH 129
Cdd:cd16191     2 FKNIFQKLAGKKC-EVTANELQTILNRVLSKrkdiksdgFTINTCREMISLLDTDGTGTLGLVEFRILWM---KIQKYLA 77

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2526894183 130 LYKAFqyfDKDHSGFITRDELETAMKEYGMGDDATIREIISEVDTDNDGRINYEEFCT-MMR 190
Cdd:cd16191    78 IYKKV---DSDRSGTIDAHEMRNALQEAGFTLNNKIQQSIVQRYASNKLTINFDGFIAcMIR 136

EF-hand, calcium binding motif, found in reticulocalbin-1 (RCN-1); RCN-1 is an endoplasmic reticulum resident low-affinity Ca2+-binding protein with six EF-hand motifs and a carboxyl-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide signal. It is expressed at the cell surface. RCN-1 acts as a potential negative regulator of B-RAF activation and can negatively modulate cardiomyocyte hypertrophy by inhibition of the mitogen-activated protein kinase signaling cascade. It also plays a key role in the development of doxorubicin-associated resistance.

Pssm-ID: 320027 [Multi-domain] Cd Length: 267 Bit Score: 44.49 E-value: 1.24e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  52 EEEIKGLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVTATM------------ 119
Cdd:cd16229    31 EESKERLGKIVDRIDDDKDGFVTTEELKAWIKRVQKRYIYENVAKVWKDYDLNKDNKISWEEYKQATYgyylgnpeefqd 110

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183 120 ------HQHKLERDEHLYKAfqyFDKDHSGFITRDELETAM--KEYGMGDDATIREIISEVDTDNDGRINYEEFCTMMRS 191
Cdd:cd16229   111 atdqfsFKKMLPRDERRFKA---ADLDGDLAATREEFTAFLhpEEFEHMKDIVVLETLEDIDKNGDGFVDEDEYIADMFS 187

Eps15 homology domain; found in proteins implicated in endocytosis, vesicle transport, and signal transduction. The alignment contains a pair of EF-hand motifs, typically one of them is canonical and binds to Ca2+, while the other may not bind to Ca2+. A hydrophobic binding pocket is formed by residues from both EF-hand motifs. The EH domain binds to proteins containing NPF (class I), [WF]W or SWG (class II), or H[TS]F (class III) sequence motifs.

Pssm-ID: 238009 [Multi-domain] Cd Length: 67 Bit Score: 41.44 E-value: 1.39e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 2526894183  62 FTNIDTDKSGTITYEELKTGLARlgSRLSEAEVEQLMEAADVDGNGTIDYIEFVTAtMH 120
Cdd:cd00052     5 FRSLDPDGDGLISGDEARPFLGK--SGLPRSVLAQIWDLADTDKDGKLDKEEFAIA-MH 60

EF-hand domain;

Pssm-ID: 463869 [Multi-domain] Cd Length: 30 Bit Score: 39.85 E-value: 2.12e-05

                          10        20
                  ....*....|....*....|....*....
gi 2526894183 130 LYKAFQYFDKDHSGFITRDELETAMKEYG 158
Cdd:pfam13405   2 LREAFKLFDKDGDGKISLEELRKALRSLG 30

Penta-EF hand, calcium binding motifs, found in mu-type calpain (CAPN1); CAPN1, also termed calpain-1 80-kDa catalytic subunit, or calpain-1 large subunit, or micromolar-calpain (muCANP), or calcium-activated neutral proteinase 1 (CANP 1), or cell proliferation-inducing gene 30 protein, is a ubiquitously expressed 80-kDa Ca2+-dependent intracellular cysteine protease that contains a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain. The catalytic subunit CAPN1 in complex with a regulatory subunit encoded by CAPNS1 forms a mu-calpain heterodimer. CAPN1 plays a central role in postmortem proteolysis and meat tenderization processes, as well as in regulation of proliferation and survival of skeletal satellite cells. It also acts as a novel regulator in IgE-mediated mast cell activation and could serve as a potential therapeutic target for the management of allergic inflammation. Moreover, CAPN1 is involved in neutrophil motility and functions as a potential target for intervention in inflammatory disease. It also facilitates age-associated aortic wall calcification and fibrosis through the regulation of matrix metalloproteinase 2 activity in vascular smooth muscle cells, and thus plays a role in hypertension and atherosclerosis. The proteolytic cleavage of beta-amyloid precursor protein and tau protein by CAPN1 may be involved in plaque formation. Furthermore, CAPN1 is activated in the brains of individuals with Alzheimer's disease. It is involved in the maintenance of a proliferative neural stem cell pool. The activation and macrophage inflammation of CAPN1 in hypercholesterolemic nephropathy is promoted by nicotinic acetylcholine receptor alpha1 (nAChRalpha1). In addition, CAPN1 displays a functional role in hemostasis, as well as in sickle cell disease.

Pssm-ID: 320073 [Multi-domain] Cd Length: 169 Bit Score: 42.87 E-value: 2.72e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  19 KPIDSAVLSRMKQFRT--------------MNKLKQLALKVIAENLSEEEIKGLKAVFTNIDTDKSGTITYEELKTGLAR 84
Cdd:cd16198    22 KTILNRIISKHKDLRTdgfslescrsmvnlMDKDGNGKLGLVEFNILWNKIRNYLTIFRKFDLDKSGSMSAYEMRLALES 101

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2526894183  85 LGSRLSEaEVEQLMEAADVDGNGTIDYIEFVTAtmhqhkLERDEHLYKAFQYFDKDHSGFITRDELE 151
Cdd:cd16198   102 AGFKLNN-RLHQVIVARYADPNLAIDFDNFVCC------LVRLETMFRFFKQLDTEETGTIEMDLFE 161

Penta-EF hand, calcium binding motifs, found in sorcin, grancalcin, and similar proteins; The family corresponds to the second group of penta-EF hand (PEF) proteins that includes sorcin, grancalcin, and similar proteins. Sorcin, also termed 22 kDa Ca2+-binding protein, CP-22, or V19, is a soluble resistance-related calcium-binding protein that is expressed in normal mammalian tissues, such as the liver, lungs and heart. It contains a flexible glycine and proline-rich N-terminal extension and five EF-hand motifs that associate with membranes in a calcium-dependent manner. It may harbor three potential Ca2+ binding sites through its EF1, EF2 and EF3 hands. However, binding of only two Ca2+/monomer suffices to trigger the conformational change that exposes hydrophobic regions and leads to interaction with the respective targets. Sorcin forms homodimers through the association of the unpaired EF5 hand. Among the PEF proteins, sorcin is unique in that it contains potential phosphorylation sites by cAMP-dependent protein kinase (PKA), and it can form a tetramer at slightly acid pH values although remaining a stable dimer at neutral pH. Grancalcin (GCA) is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It can strongly interact with sorcin to form a heterodimer and further modulate the function of sorcin. GCA exists as homodimers in solution. It contains five EF-hand motifs attached to an N-terminal region of an approximately 50 residue-long segment rich in glycines and prolines. In contrast with sorcin, GCA binds two Ca2+ ions through its EF1 and EF3 hands.

Pssm-ID: 320056 [Multi-domain] Cd Length: 165 Bit Score: 42.36 E-value: 3.22e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 2526894183  57 GLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVdgNGTIDYIEFV 115
Cdd:cd16181    71 QWKTTFMQYDRDRSGTVEPQELQQAIRSFGYNLSPQALNVIVKRYSK--NGRITFDDFV 127

Eps15 homology domain; Pair of EF hand motifs that recognise proteins containing Asn-Pro-Phe (NPF) sequences.

Pssm-ID: 197477 [Multi-domain] Cd Length: 96 Bit Score: 41.11 E-value: 3.40e-05

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2526894183   50 LSEEEIKGLKAVFTNIDTDKSGTITYEELKTGLARlgSRLSEAEVEQLMEAADVDGNGTIDYIEFVTAtMH 120
Cdd:smart00027   4 ISPEDKAKYEQIFRSLDKNQDGTVTGAQAKPILLK--SGLPQTLLAKIWNLADIDNDGELDKDEFALA-MH 71

Penta-EF hand, calcium binding motifs, found in calcium-dependent protease small subunit CAPNS1 and CAPNS2; CAPNS1, also termed calpain small subunit 1 (CSS1), or calcium-activated neutral proteinase small subunit (CANP small subunit), or calcium-dependent protease small subunit (CDPS), or calpain regulatory subunit, is a common 28-kDa regulatory calpain subunit encoded by the calpain small 1 (Capns1, also known as Capn4) gene. It acts as a binding partner to form a heterodimer with the 80 kDa calpain large catalytic subunit and is required in maintaining the activity of calpain. CAPNS1 plays a significant role in tumor progression of human cancer, and functions as a potential therapeutic target in human hepatocellular carcinoma (HCC), nasopharyngeal carcinoma (NPC), glioma, and clear cell renal cell carcinoma (ccRCC). It may be involved in regulating migration and cell survival through binding to the SH3 domain of Ras GTPase-activating protein (RasGAP). It may also modulate Akt/FoxO3A signaling and apoptosis through PP2A. CAPNS1 contains an N-terminal glycine rich domain and a C-terminal PEF-hand domain. CAPNS2, also termed calpain small subunit 2 (CSS2), is a novel tissue-specific 30 kDa calpain small subunit that lacks two oligo-Gly stretches characteristic of the N-terminal Gly-rich domain of CAPNS1. CAPNS2 acts as a chaperone for the calpain large subunit, and appears to be the functional equivalent of CAPNS1. However, CAPNS2 binds the large subunit much more weakly than CAPNS1 and it does not undergo the autolytic conversion typical of CAPNS1.

Pssm-ID: 320063 [Multi-domain] Cd Length: 169 Bit Score: 42.42 E-value: 3.84e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  55 IKGLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEaEVEQLMEAADVDGNGTIDYIEFVTAtmhqhkLERDEHLYKAF 134
Cdd:cd16188    72 IKKWQGIYKQFDTDRSGTIGSQELPGAFEAAGFHLNE-QLYQMIIRRYSDEDGNMDFDNFISC------LVRLDAMFRAF 144

                          90
                  ....*....|.
gi 2526894183 135 QYFDKDHSGFI 145
Cdd:cd16188   145 KSLDKDGTGQI 155

EF-hand, calcium binding motif, found in peflin and similar proteins; Peflin, also termed penta-EF hand (PEF) protein with a long N-terminal hydrophobic domain, or penta-EF hand domain-containing protein 1, is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. In lower vertebrates, peflin may interact with transient receptor potential N (TRPN1), suggesting a potential role of peflin in fast transducer channel adaptation.

Pssm-ID: 320059 [Multi-domain] Cd Length: 165 Bit Score: 42.25 E-value: 4.06e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2526894183 130 LYKAFQYFDKDHSGFITRDELETAM--KEYGMGDDATIREIISEVDTDNDGRINYEEF 185
Cdd:cd16184     2 VQQWFQAVDRDRSGKISAKELQQALvnGNWSHFNDETCRLMIGMFDKDKSGTIDIYEF 59

EF-hand, calcium binding motif, found in alpha-parvalbumin; Alpha-parvalbumin is cytosolic Ca2+/Mg2+-binding protein expressed mainly in fast-twitch skeletal myofibrils, where it may act as a soluble relaxing factor facilitating the Ca2+-mediated relaxation phase. It is also expressed in rapidly firing neurons, particularly GABA-ergic neurons, and thus may confer protection against Ca2+ toxicity. The major role of alpha-parvalbumin is metal buffering and transport of Ca2+. It binds different metal cations, and exhibits very high affinity for Ca2+ and physiologically significant affinity for Mg2+. Alpha-parvalbumin is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Both metal ion-binding sites in alpha-parvalbumin are high-affinity sites. Additionally, in contrast to beta-parvalbumin, alpha-parvalbumin is less acidic and has an additional residue in the C-terminal helix.

Pssm-ID: 319997 [Multi-domain] Cd Length: 101 Bit Score: 40.96 E-value: 4.42e-05

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2526894183 123 KLERDEHLYKAFQYFDKDHSGFITRDELETAMKEYGMG----DDATIREIISEVDTDNDGRINYEEFCTMM 189
Cdd:cd16254    29 KKKSADDVKKVFHILDKDKSGFIEEDELKFVLKGFSPDgrdlSDKETKALLAAGDKDGDGKIGIDEFATLV 99

EF-hand domain pair;

Pssm-ID: 404678 [Multi-domain] Cd Length: 54 Bit Score: 39.61 E-value: 4.45e-05

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 2526894183  69 KSGTITYEELKTGLARLG-SRLSEAEVEQLMEAADVDGNGTIDYIEFVTATMHQ 121
Cdd:pfam13833   1 EKGVITREELKRALALLGlKDLSEDEVDILFREFDTDGDGYISFDEFCVLLERR 54

Penta-EF hand, calcium binding motifs, found in PEF calpain family; The PEF calpain family belongs to the second group of penta-EF hand (PEF) proteins. It includes classical (also called conventional or typical) calpain (referring to a calcium-dependent papain-like enzymes, EC 3.4.22.17) large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14) and two calpain small subunits (CAPNS1 and CAPNS2), which are largely confined to animals (metazoans). These PEF-containing are nonlysosomal intracellular calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates in response to calcium signalling. The classical mu- and m-calpains are heterodimers consisting of homologous but a distinct (large) L-subunit/chain (CAPN1 or CAPN2) and a common (small) S-subunit/chain (CAPNS1 or CAPNS2). These L-subunits (CAPN1 and CAPN2) and S-subunit CAPNS1 are ubiquitously found in all tissues. Other calpains likely consist of an isolated L-subunit/chain alone. Many of them, such as CAPNS2, CAPN3 (in skeletal muscle, or lens), CAPN8 (in stomach), CAPN9 (in digestive tracts), CAPN11 (in testis), CAPN12 (in follicles), are tissue-specific and have specific functions in distinct organs. The L-subunits of similar structure (called CALPA and B) also have been found in Drosophila melanogaster. The S-subunit seems to have a chaperone-like function for proper folding of the L-subunit. The catalytic L-subunits contain a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain. The S-subunits only have the PEF domain following an N-terminal Gly-rich hydrophobic domain. The calpains undergo a rearrangement of the protein backbone upon Ca2+-binding.

Pssm-ID: 320057 [Multi-domain] Cd Length: 167 Bit Score: 41.83 E-value: 5.08e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  96 QLMEAADVDGNGTIDYIEFvtatmhQHKLERDEHLYKAFQYFDKDHSGFITRDELETAMKEYGMGDDATIREIISEVDTD 175
Cdd:cd16182    46 SLIALMDTNGSGRLDLEEF------KTLWSDLKKWQAIFKKFDTDRSGTLSSYELRKALESAGFHLSNKVLQALVLRYAD 119

                          90
                  ....*....|
gi 2526894183 176 NDGRINYEEF 185
Cdd:cd16182   120 STGRITFEDF 129

EF-hand, calcium binding motif, found in 45 kDa calcium-binding protein (Cab45); Cab45, also termed stromal cell-derived factor 4 (SDF-4), is a soluble, lumenal Golgi resident low-affinity Ca2+-binding protein that contains six copies of the EF-hand Ca2+-binding motif. It is required for secretory pathway calcium ATPase1 (SPCA1)-dependent Ca2+ import into the trans-Golgi network (TGN) and plays an essential role in Ca2+-dependent secretory cargo sorting at the TGN.

Pssm-ID: 320023 [Multi-domain] Cd Length: 278 Bit Score: 42.29 E-value: 7.97e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  48 ENLSEEEIKG-LKAVFTNIDTDKSGTITYEELKTG-LARLGSRLSEA--EVEQLMEAADVDGNGTIDYIEFvtatmHQHK 123
Cdd:cd16225    25 EEDSEPKKRKkLKEIFKKVDVNTDGFLSAEELEDWiMEKTQEHFQEAveENEQIFKAVDTDKDGNVSWEEY-----RVHF 99

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2526894183 124 LERDEH-LYKAFQYFDKDHSGFITRDELETAMKEYGMGDDAtireiisevDTDNDGRINYEEF 185
Cdd:cd16225   100 LLSKGYsEEEAEEKIKNNEELKLDEDDKEVLDRYKDRWSQA---------DEPEDGLLDVEEF 153

Calcium-activated neutral; CAPN3, also termed calcium-activated neutral proteinase 3 (CANP 3), or calpain L3, or calpain p94, or muscle-specific calcium-activated neutral protease 3, or new calpain 1 (nCL-1), is a calpain large subunit that is mainly expressed in skeletal muscle, or lens. The skeletal muscle-specific CAPN3 are pathologically associated with limb girdle muscular dystrophy type 2A (LGMD2A). Its autolytic activity can be positively regulated by calmodulin (CaM), a known transducer of the calcium signal. CAPN3 is also involved in human melanoma tumorigenesis and progression. It impairs cell proliferation and stimulates oxidative stress-mediated cell death in melanoma cells. Moreover, it plays an important role in sarcomere remodeling and mitochondrial protein turnover. Furthermore, the phosphorylated skeletal muscle-specific CAPN3 acts as a myofibril structural component and may participate in myofibril-based signaling pathways. In the eye, the lens-specific CAPN3, together with CAPN2, is responsible for proteolytic cleavages of alpha and beta-crystallin. Overactivated alpha and beta-crystallin can lead to cataract formation. CAPN3 exists as a homodimer, rather than a heterodimer with the calpain small subunit. It may also form heterodimers with other calpain large subunits. CAPN3 contains a long N-terminal region, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain. Ca2+ binding at EF5 of the CAPN3 PEF domain is a distinct feature not observed in other calpain isoforms.

Pssm-ID: 320065 [Multi-domain] Cd Length: 169 Bit Score: 41.38 E-value: 8.46e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  59 KAVFTNIDTDKSgTITYEELKTGLARLGSRLSEAEVE--------QLMEAADVDGNGTIDYIEFvtatmhQHKLERDEHL 130
Cdd:cd16190     3 RNIFQQIAGDDM-EISADELRSVLNRVVKKHKDLKTEgftlescrSMIALMDTDGSGKLNLQEF------RHLWNKIKQW 75

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2526894183 131 YKAFQYFDKDHSGFITRDELETAMKEYGMGDDATIREIISEVDTDNDGRINYEEF--CTMMRSGM 193
Cdd:cd16190    76 QKIFKRYDTDKSGTINSYEMRNAVNDAGFRLNNQLYDIITMRYADKHMNIDFDSFicCFVRLEGM 140

Penta-EF hand, calcium binding motifs, found in calpain-8 (CAPN8); CAPN8, also termed new calpain 2 (nCL-2), or stomach-specific M-type calpain, is a calpain large subunit predominantly expressed in the stomach. It appears to be involved in membrane trafficking in the gastric surface mucus cells (pit cells), via its location at the Golgi and interaction with the beta-subunit of coatomer complex (beta-COP) of vesicles derived from the Golgi. Moreover, CAPN8, together with CAPN9, forms an active protease complex, G-calpain, in which both proteins are essential for stability and activity. The G-Calpain has been implicated in gastric mucosal defense. CAPN8 exists as both a monomer and homo-oligomer, but not as a heterodimer with the conventional calpain regulatory subunit (30K). The monomer and homodimer forms predominate. CAPN8 contains a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain.

Pssm-ID: 320066 [Multi-domain] Cd Length: 168 Bit Score: 41.31 E-value: 8.84e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  60 AVFTNIDTDKSGTITYEELKTGLARLGSRLSEaEVEQLMEAADVDGNGTIDYIEFVTATMhqhkleRDEHLYKAFQYFDK 139
Cdd:cd16191    77 AIYKKVDSDRSGTIDAHEMRNALQEAGFTLNN-KIQQSIVQRYASNKLTINFDGFIACMI------RLETLFKMFQLLDK 149


                  ....*.
gi 2526894183 140 DHSGFI 145
Cdd:cd16191   150 DKSGVV 155

EF-hand motif found in phosphoinositide phospholipase C delta (PI-PLC-delta); PI-PLC-delta isozymes represent a class of metazoan PI-PLCs that are some of the most sensitive to calcium among all PLCs. Their activation is modulated by intracellular calcium ion concentration, phospholipids, polyamines, and other proteins, such as RhoAGAP. Like other PI-PLC isozymes, PI-PLC-delta isozymes contain a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C-terminal C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There are three PI-PLC-delta isozymes (1, 3 and 4). PI-PLC-delta1 is relatively well characterized. It is activated by high calcium levels generated by other PI-PLC family members, and therefore functions as a calcium amplifier within the cell. Different PI-PLC-delta isozymes have different tissue distribution and different subcellular locations. PI-PLC-delta1 is mostly a cytoplasmic protein, PI-PLC-delta3 is located in the membrane, and PI-PLC-delta4 is predominantly detected in the cell nucleus. PI-PLC-delta isozymes is evolutionarily conserved even in non-mammalian species, such as yeast, slime molds and plants.

Pssm-ID: 320032 [Multi-domain] Cd Length: 140 Bit Score: 40.67 E-value: 9.23e-05

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  58 LKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVtaTMHQHKLERDEhLYKAFQYF 137
Cdd:cd16202     2 LKDQFRKADKNGDGKLSFKECKKLLKKLNVKVDKDYAKKLFQEADTSGEDVLDEEEFV--QFYNRLTKRPE-IEELFKKY 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 2526894183 138 DKDhSGFITRDELETAM-KEYGMGDDATIR--EIISEVDTDNDGRIN 181
Cdd:cd16202    79 SGD-DEALTVEELRRFLqEEQKVKDVTLEWaeQLIETYEPSEDLKAQ 124

Penta-EF hand, calcium binding motifs, found in sorcin, grancalcin, and similar proteins; The family corresponds to the second group of penta-EF hand (PEF) proteins that includes sorcin, grancalcin, and similar proteins. Sorcin, also termed 22 kDa Ca2+-binding protein, CP-22, or V19, is a soluble resistance-related calcium-binding protein that is expressed in normal mammalian tissues, such as the liver, lungs and heart. It contains a flexible glycine and proline-rich N-terminal extension and five EF-hand motifs that associate with membranes in a calcium-dependent manner. It may harbor three potential Ca2+ binding sites through its EF1, EF2 and EF3 hands. However, binding of only two Ca2+/monomer suffices to trigger the conformational change that exposes hydrophobic regions and leads to interaction with the respective targets. Sorcin forms homodimers through the association of the unpaired EF5 hand. Among the PEF proteins, sorcin is unique in that it contains potential phosphorylation sites by cAMP-dependent protein kinase (PKA), and it can form a tetramer at slightly acid pH values although remaining a stable dimer at neutral pH. Grancalcin (GCA) is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It can strongly interact with sorcin to form a heterodimer and further modulate the function of sorcin. GCA exists as homodimers in solution. It contains five EF-hand motifs attached to an N-terminal region of an approximately 50 residue-long segment rich in glycines and prolines. In contrast with sorcin, GCA binds two Ca2+ ions through its EF1 and EF3 hands.

Pssm-ID: 320056 [Multi-domain] Cd Length: 165 Bit Score: 40.43 E-value: 1.88e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  71 GTITYEELKTGLARLG-----SRLSeAEVEQLMEAA-DVDGNGTIDYIEF--VTATMHQHKlerdehlyKAFQYFDKDHS 142
Cdd:cd16181    14 GQIDADELQRCLTQSGisgnyQPFS-LETCRLMIAMlDRDHSGKMGFNEFkeLWAALNQWK--------TTFMQYDRDRS 84

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 2526894183 143 GFITRDELETAMKEYGMG-DDATIREIISEVdtDNDGRINYEEF 185
Cdd:cd16181    85 GTVEPQELQQAIRSFGYNlSPQALNVIVKRY--SKNGRITFDDF 126

EF-hand, calcium binding motif, found in mitochondrial calcium uptake proteins MICU1, MICU2, MICU3, and similar proteins; This family includes mitochondrial calcium uptake protein MICU1 and its two additional paralogs, MICU2 and MICU3. MICU1 localizes to the inner mitochondrial membrane (IMM). It functions as a gatekeeper of the mitochondrial calcium uniporter (MCU) and regulates MCU-mediated mitochondrial Ca2+ uptake, which is essential for maintaining mitochondrial homoeostasis. MICU1 and MICU2 are physically associated within the uniporter complex and are co-expressed across all tissues. They may play non-redundant roles in the regulation of the mitochondrial calcium uniporter. At present, the precise molecular function of MICU2 and MICU3 remain unclear. MICU2 may play possible roles in Ca2+ sensing and regulation of MCU, calcium buffering with a secondary impact on transport or assembly and stabilization of MCU. MICU3 likely has a role in mitochondrial calcium handling. All members in this family contains an N-terminal mitochondrial targeting sequence (MTS) as well as two evolutionarily conserved canonical Ca2+-binding EF-hands separated by a long stretch of residues predicted to form alpha-helices.

Pssm-ID: 320080 [Multi-domain] Cd Length: 152 Bit Score: 40.29 E-value: 1.91e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183 102 DVDGNGTIDYIEFVT------------------ATMHQHKLERDEHLYKAFqyFDKDHSG---------FITR-----DE 149
Cdd:cd15900    10 DLDGDGELDKEEFNKvqsiirsqtsvgqrhrdhTNGESTKLGMNSTLARYF--FGKDGKQklsiekfleFQENlqeeiDD 87

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2526894183 150 LETAMKEYGMG----DDATIREIISEV-----------------DTDNDGRINYEEFCTMMRSGM 193
Cdd:cd15900    88 VDTALTFYHLAgasiDRKTFKRAAKVVagvelsdhvvdvvftifDEDGDGILSHKEFISVMKDRL 152

EF-hand, calcium binding motif, found in calumenin, reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins; The family corresponds to a group of six EF-hand Ca2+-binding proteins, including calumenin (also known as crocalbin or CBP-50), reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins. Calumenin is an endo/sarcoplasmic reticulum (ER/SR) resident low-affinity Ca2+-binding protein that contains six EF-hand domains and a C-terminal SR retention signal His-Asp-Glu-Phe (HDEF) tetrapeptide. It functions as a novel regulator of SERCA2, and its expressional changes are tightly coupled with Ca2+-cycling of cardiomyocytes. It is also broadly involved in haemostasis and in the pathophysiology of thrombosis. Moreover, the extracellular calumenin acts as a suppressor of cell migration and tumor metastasis. RCN-1 is an endoplasmic reticulum resident Ca2+-binding protein with a carboxyl-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide signal. It acts as a potential negative regulator of B-RAF activation and can negatively modulate cardiomyocyte hypertrophy by inhibition of the mitogen-activated protein kinase signalling cascade. It also plays a key role in the development of doxorubicin-associated resistance. RCN-3 is a putative six EF-hand Ca2+-binding protein that contains five RXXR (X is any amino acid) motifs and a C-terminal ER retrieval signal HDEL tetrapeptide. The RXXR motif represents the target sequence of subtilisin-like proprotein convertases (SPCs). RCN-3 is specifically bound to the paired basic amino-acid-cleaving enzyme-4 (PACE4) precursor protein and plays an important role in the biosynthesis of PACE4.

Pssm-ID: 320024 [Multi-domain] Cd Length: 264 Bit Score: 41.03 E-value: 2.00e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  66 DTDKSGTITYEELKTGL-ARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVtATMHQHKLERDEHLY-----KAFQ-YFD 138
Cdd:cd16226   129 DQDGDGKLTKEEFTAFLhPEEFPHMRDIVVQETLEDIDKNKDGFISLEEYI-GDMYRDDDEEEDPDWvkserEQFKeFRD 207

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2526894183 139 KDHSGFITRDEletaMKEYGMGDD-----ATIREIISEVDTDNDGRINYEE 184
Cdd:cd16226   208 KNKDGKMDREE----VKDWILPEDydhaeAEAKHLIYEADDDKDGKLTKEE 254

Penta-EF hand, calcium binding motifs, found in calpain-13 (CAPN13), calpain-14 (CAPN14), and similar proteins; CAPN13, also termed calcium-activated neutral proteinase 13 (CANP 13), a 63.6 kDa calpain large subunit that exhibits a restricted tissue distribution with low levels of expression detected only in human testis and lung. In calpain family, CAPN13 is most closely related to calpain-14 (CAPN14). CAPN14, also termed calcium-activated neutral proteinase 14 (CANP 14), is a 76.7 kDa calpain large subunit that is most highly expressed in the oesophagus. Its expression and calpain activity can be induced by IL-13. Both CAPN13 and CAPN14 contain a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain.

Pssm-ID: 320070 [Multi-domain] Cd Length: 168 Bit Score: 39.88 E-value: 2.59e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  50 LSEEEIKGL-------KAVFTNIDTDKSGTITYEELKTGLARLGSRLSEaEVEQLMEAADVDGNGTIDYIEFVTATMhqh 122
Cdd:cd16195    60 LSLEEFSRLwkklrkyKDIFQKADVSKSGFLSLSELRNAIQAAGIRVSD-DLLNLMALRYGDSSGRISFESFICLML--- 135

                          90
                  ....*....|....*...
gi 2526894183 123 KLERdehLYKAFQYFDKD 140
Cdd:cd16195   136 RLEC---MAKIFRNLSKD 150

Penta-EF hand, calcium binding motifs, found in m-type calpain (CAPN2); CAPN2, also termed millimolar-calpain (m-calpain), or calpain-2 catalytic subunit, or calcium-activated neutral proteinase 2 (CANP 2), or calpain large polypeptide L2, or calpain-2 large subunit, is a ubiquitously expressed 80-kDa Ca2+-dependent intracellular cysteine protease that contains a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain. The catalytic subunit CAPN2 in complex with a regulatory subunit encoded by CAPNS1 forms an m-calpain heterodimer. CAPN2 acts as the key protease responsible for N-methyl-d-aspartic acid (NMDA)-induced cytoplasmic polyadenylation element-binding protein 3 (CPEB3) degradation in neurons. It cleaves several components of the focal adhesion complex, such as FAK and talin, triggering disassembly of the complex at the rear of the cell. The stimulation of CAPN2 activity is required for Golgi antiapoptotic proteins (GAAPs) to promote cleavage of FA kinase (FAK), cell spreading, and enhanced migration. calpain 2 is also involved in the onset of glial differentiation. It regulates proliferation, survival, migration, and tumorigenesis of breast cancer cells through a PP2A-Akt-FoxO-p27(Kip1) signaling cascade. Its expression is associated with response to platinum based chemotherapy, progression-free and overall survival in ovarian cancer. Moreover, CAPN2 may play a role in fundamental mitotic functions, such as the maintenance of sister chromatid cohesion. The activation of CAPN2 plays an essential role in hippocampal synaptic plasticity and in learning and memory. In the eye, CAPN2, together with a lens-specific variant of CAPN3, is responsible for proteolytic cleavages of alpha and beta-crystallin. Overactivated alpha and beta-crystallin can lead to cataract formation. Sometimes, CAPN2 compensates for loss of CAPN1, and both calpain isoforms are involved in AngII-induced aortic aneurysm formation. The main phosphorylation sites in m-calpain are Ser50 and Ser369/Thr370.

Pssm-ID: 320074 [Multi-domain] Cd Length: 168 Bit Score: 39.50 E-value: 3.49e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  54 EIKGLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSeAEVEQLMEAADVDGNGTIDYIEFVTAtmhqhkLERDEHLYKA 133
Cdd:cd16199    71 KIQKYQKIYREIDVDRSGTMNSYEMRKALEEAGFKLP-CQLHQVIVARFADDDLIIDFDNFVRC------LVRLETLFKI 143

                          90
                  ....*....|..
gi 2526894183 134 FQYFDKDHSGFI 145
Cdd:cd16199   144 FKQLDPENTGTI 155

EF-hand motif found in Saccharomyces cerevisiae phospholipase C-1 (ScPlc1p) and similar proteins; This family represents a group of putative phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11) encoded by PLC1 genes from yeasts, which are homologs of the delta isoforms of mammalian PI-PLC in terms of overall sequence similarity and domain organization. Mammalian PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. The prototype of this family is protein Plc1p (also termed 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase 1) encoded by PLC1 genes from Saccharomyces cerevisiae. ScPlc1p contains both highly conserved X- and Y- regions of PLC catalytic core domain, as well as a presumptive EF-hand like calcium binding motif. Experiments show that ScPlc1p displays calcium dependent catalytic properties with high similarity to those of the mammalian PLCs, and plays multiple roles in modulating the membrane/protein interactions in filamentation control. CaPlc1p encoded by CAPLC1 from the closely related yeast Candida albicans, an orthologue of S. cerevisiae Plc1p, is also included in this group. Like SCPlc1p, CaPlc1p has conserved presumptive catalytic domain, shows PLC activity when expressed in E. coli, and is involved in multiple cellular processes. There are two other gene copies of CAPLC1 in C. albicans, CAPLC2 (also named as PIPLC) and CAPLC3. Experiments show CaPlc1p is the only enzyme in C. albicans which functions as PLC. The biological functions of CAPLC2 and CAPLC3 gene products must be clearly different from CaPlc1p, but their exact roles remain unclear. Moreover, CAPLC2 and CAPLC3 gene products are more similar to extracellular bacterial PI-PLC than to the eukaryotic PI-PLC, and they are not included in this subfamily.

Pssm-ID: 320037 [Multi-domain] Cd Length: 142 Bit Score: 39.15 E-value: 3.53e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  49 NLSEEEikgLKAVFTNIDTDKSGTITYEELKTGLARLGSRlseAEVEQLMEAADVDGNGTIDYIEFVT-ATMHQHKLERD 127
Cdd:cd16207    34 NCSESY---LRELFDKADTDKKGYLNFEEFQEFVKLLKRR---KDIKAIFKQLTKPGSDGLTLEEFLKfLRDVQKEDVDR 107

                          90       100
                  ....*....|....*....|....*..
gi 2526894183 128 EHLYKAFQYF----DKDHSGFITRDEL 150
Cdd:cd16207   108 ETWEKIFEKFarriDDSDSLTMTLEGF 134

EF-hand, calcium binding motif, found in reticulocalbin-3 (RCN-3); RCN-3, also termed EF-hand calcium-binding protein RLP49, is a putative six EF-hand Ca2+-binding protein that contains five RXXR (X is any amino acid) motifs and a C-terminal ER retrieval signal His-Asp-Glu-Leu (HDEL) tetrapeptide. The RXXR motif represents the target sequence of subtilisin-like proprotein convertases (SPCs). RCN-3 is specifically bound to the paired basic amino-acid-cleaving enzyme-4 (PACE4) precursor protein and plays an important role in the biosynthesis of PACE4.

Pssm-ID: 320028 [Multi-domain] Cd Length: 268 Bit Score: 40.34 E-value: 3.78e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  58 LKAVFTNIDTDKSGTITYEELKtglarlgsRLSEAEVEQLMEAADVDgngtidyiefvTATMHQHKLERDEhlyKAFQYF 137
Cdd:cd16230    75 VSAAWQTYDTDRDGRVGWEELR--------NATYGHYEPGEEFHDVE-----------DAETYKKMLARDE---RRFRVA 132

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 2526894183 138 DKDHSGFITRDELETAM--KEYGMGDDATIREIISEVDTDNDGRINYEEFCTMMRSG 192
Cdd:cd16230   133 DQDGDSMATREELTAFLhpEEFPHMRDIVVAETLEDLDKNKDGYVQVEEYIADLYSG 189

EF-hand, calcium binding motif, found in Drosophila melanogaster calbindin-32 (CBN) and similar proteins; CBN, the product of the cbn gene, is a Drosophila homolog to vertebrate neuronal six EF-hand calcium binding proteins. It is expressed through most of ontogenesis with a selective distribution in the nervous system and in a few small adult thoracic muscles. Its precise biological role remains unclear. CBN contains six EF-hand motifs, but some of them may not bind calcium ions due to the lack of key residues.

Pssm-ID: 320079 [Multi-domain] Cd Length: 261 Bit Score: 39.70 E-value: 4.56e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  61 VFTNIDTDKSGTITYEELKTGLARLGSR----------LSEAEVEQL----MEAADVDGNGTIDYIE----------FVT 116
Cdd:cd16179     4 VWNHYDTDGNGYIEGTELDGFLREFVSSvnpedvgpevVSETALEELkeefMEAYDENQDGRIDIRElaqllpteenFLL 83

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2526894183 117 ATMHQHKLERDEHLYKAFQYFDKDHSGFITRDELETAMKEYgmgddatIREIISEVDTDNDGRINYEEfcTMMR 190
Cdd:cd16179    84 LFRRDNPLDSSVEFMKVWREYDKDNSGYIEADELKNFLKHL-------LKEAKRDNDVSEDKLIEYTD--TILQ 148

EF-hand, calcium binding motif, found in secretagogin (SCGN); SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a calcium sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. It also serves as a calcium buffer in neurons. Thus, SCGN may be linked to the pathogenesis of neurological diseases such as Alzheimer's, and also acts as a serum marker of neuronal damage, or as a tumor biomarker. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. All six EF hand motifs of SCGN in some eukaryotes, including D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, could potentially bind six calcium ions. In contrast, SCGNs from higher eukaryotes have at least one non-functional EF-hand motif due to the mutation(s) or deletions. For instance, the EF1 loop does not coordinate calcium ion due to the key residue asparagine replaced by lysine in SCGNs of many mammalian species. Moreover, the EF2 loop seems to be competent for calcium-binding in most mammalian SCGNs except for human and chimpanzee orthologs.

Pssm-ID: 320078 [Multi-domain] Cd Length: 257 Bit Score: 39.31 E-value: 7.22e-04

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  66 DTDKSGTITYEELKTGLARL----GSRLSEAEVEQ----LMEAADVDGNGTIDYIEFV------TATMHQHKL------E 125
Cdd:cd16178   102 DADSSGYISAAELKNFLRDLflqhKKVITEDKLDEytdtMMKIFDKNKDGRLDLNDMArilalqENFLLQFKMdamseeE 181

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 2526894183 126 RDEHLYKAFQYFDKDHSGFITRDEL--------ETAMKEYGMGDDATIREII-SEVDTDNDGRINYEE 184
Cdd:cd16178   182 RKRDFEKIFAHYDVSKTGALEGPEVdgfvkdmmELVKPSISGVQLDKFKEIIlNHCDVNKDGKIQKSE 249

EF hand; The EF-hands can be divided into two classes: signalling proteins and buffering/transport proteins. The first group is the largest and includes the most well-known members of the family such as calmodulin, troponin C and S100B. These proteins typically undergo a calcium-dependent conformational change which opens a target binding site. The latter group is represented by calbindin D9k and do not undergo calcium dependent conformational changes.

Pssm-ID: 425435 [Multi-domain] Cd Length: 29 Bit Score: 35.45 E-value: 8.07e-04

                          10        20
                  ....*....|....*....|....*...
gi 2526894183 129 HLYKAFQYFDKDHSGFITRDELETAMKE 156
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKK 28

transaldolase;

Pssm-ID: 183426 [Multi-domain] Cd Length: 391 Bit Score: 39.33 E-value: 9.62e-04

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2526894183 123 KLERDEHLYKA----FQYFDKDHSGFITRDELetamkeygMGDDAtireIISEVDTDNDGRINYEEfctmMRSGM 193
Cdd:PRK12309  325 RLEGGEAFTHAaqeiFRLYDLDGDGFITREEW--------LGSDA----VFDALDLNHDGKITPEE----MRAGL 383

Penta-EF hand, calcium binding motifs, found in sorcin; Sorcin, also termed 22 kDa Ca2+-binding protein, CP-22, or V19, is a soluble resistance-related calcium-binding protein that is expressed in normal mammalian tissues, such as the liver, lungs and heart. The up-regulation of sorcin is correlated with a number of cancer types, including colorectal, gastric and breast cancer. It may represent a therapeutic target for reversing tumor multidrug resistance (MDR). Sorcin participates in the regulation of calcium homeostasis in cells and is necessary for the activation of mitosis and cytokinesis. It enhances metastasis and promotes epithelial-to-mesenchymal transition of colorectal cancer. Moreover, sorcin has been implicated in the regulation of intracellular Ca2+ cycling and cardiac excitation-contraction coupling. It displays the anti-apoptotic properties via the modulation of mitochondrial Ca2+ handling in cardiac myocytes. It can target and activate the sarcolemmal Na+/Ca2+ exchanger (NCX1) in cardiac muscle. Meanwhile, sorcin modulates cardiac L-type Ca2+ current by functional interaction with the alpha1C subunit. It also associates with calcium/calmodulin-dependent protein kinase IIdeltaC (CaMKIIdelta(C)) and further modulates ryanodine receptor (RyR) function in cardiac myocytes. Furthermore, sorcin may act as a Ca2+ sensor for glucose-induced nuclear translocation and the activation of carbohydrate-responsive element-binding protein (ChREBP)-dependent genes. As a mitochondrial chaperone TRAP1 interactor, sorcin involves in mitochondrial metabolism through the TRAP1 pathway. In addition, sorcin may regulate the inhibition of type I interferon response in cells through interacting with foot-and-mouth disease virus (FMDV) VP1. Sorcin contains a flexible glycine and proline-rich N-terminal extension and five EF-hand motifs that associate with membranes in a calcium-dependent manner. It may harbor three potential Ca2+ binding sites through its EF1, EF2 and EF3 hands. However, binding of only two Ca2+/monomer suffices to trigger the conformational change that exposes hydrophobic regions and leads to interaction with the respective targets. Sorcin forms homodimers through the association of the unpaired EF5 hand. Among the PEF proteins, sorcin is unique in that it contains potential phosphorylation sites by cAMP-dependent protein kinase (PKA), and it can form a tetramer at slightly acid pH values although remaining a stable dimer at neutral pH.

Pssm-ID: 320062 [Multi-domain] Cd Length: 165 Bit Score: 37.58 E-value: 1.57e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 2526894183  55 IKGLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTI-DYI 112
Cdd:cd16187    69 LNGWRQHFISFDSDRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRYSTNGKITFdDYI 127

Penta-EF hand, calcium binding motifs, found in calpain-9 (CAPN9); CAPN9, also termed digestive tract-specific calpain, or new calpain 4 (nCL-4), or protein CG36, is a calpain large subunit predominantly expressed in gastrointestinal tract. It plays a physiological role in the suppression of tumorigenesis. It acts as an important biomolecule link for the regression of colorectal cancer via intracellular calcium homeostasis. CAPN9 may also play a critical role in lumen formation. Moreover, CAPN9, together with CAPN8, forms an active protease complex, G-calpain, in which both proteins are essential for stability and activity. The G-Calpain has been implicated in gastric mucosal defense. Furthermore, down-regulation of calpain 9 has been linked to hypertensive heart and kidney disease in salt-sensitive Dahl rats. CAPN9 contains a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain.

Pssm-ID: 320067 [Multi-domain] Cd Length: 169 Bit Score: 37.08 E-value: 2.54e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  53 EEIKGLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEaEVEQLMEAADVDGNGTIDYIEFVTAtmhqhkLERDEHLYK 132
Cdd:cd16192    70 DKLKKWIGLFLKYDADRSGTMSSYELRSALKAAGFQLNN-QLLQLIVLRYADDYLQIDFDDFLNC------LVRLENSFR 142

                          90
                  ....*....|....*....
gi 2526894183 133 AFQYFDKDHSGFITRDELE 151
Cdd:cd16192   143 VFQALDTKNTGEISLNMLE 161

EF-hand domain;

Pssm-ID: 463869 [Multi-domain] Cd Length: 30 Bit Score: 34.07 E-value: 2.62e-03

                          10        20
                  ....*....|....*....|....*....
gi 2526894183  58 LKAVFTNIDTDKSGTITYEELKTGLARLG 86
Cdd:pfam13405   2 LREAFKLFDKDGDGKISLEELRKALRSLG 30

Penta-EF hand, calcium binding motifs, found in Drosophila melanogaster calpain-A (CalpA), calpain-B (CalpB), and similar proteins; The family contains two calpains that have been found in Drosophila, CalpA and CalpB. CalpA, also termed calcium-activated neutral proteinase A (CANP A), or calpain-A catalytic subunit, is a Drosophila calpain homolog specifically expressed in a few neurons in the central nervous system, in scattered endocrine cells in the midgut, and in blood cells. CalpB, also termed calcium-activated neutral proteinase B (CANP B), contains calpain-B catalytic subunit 1 and calpain-B catalytic subunit 2. Both CalpA and CalpB are closely related to that of vertebrate calpains, and they share similar domain architecture, which consists of four domains: the N-terminal domain I, the catalytic domain II carrying the three active site residues, Cys, His and Asn, the Ca2+-regulated phospholipid-binding domain III, and penta-EF-hand Ca2+-binding domain IV. Besides, CalpA and CalpB display some distinguishing structural features that are not found in mammalian typical calpains. CalpA harbors a 76 amino acid long hydrophobic stretch inserted in domain IV, which may be involved in membrane attachment of this enzyme. CalpB has an unusually long N-terminal tail of 224 amino acids, which belongs to the class of intrinsically unstructured proteins (IUP) and may become ordered upon binding to target protein(s). Moreover, they do not need small regulatory subunits for their catalytic activity, and their proteolytic function is not regulated by an intrinsic inhibitor as the Drosophila genome contains neither regulatory subunit nor calpastatin orthologs. As a result, they may exist as a monomer or perhaps as a homo- or heterodimer together with a second large subunit. Furthermore, both CalpA and CalpB are dispensable for viability and fertility and do not share vital functions during Drosophila development. Phosphatidylinositol 4,5-diphosphate, phosphatidylinositol 4-monophosphate, phosphatidylinositol, and phosphatidic acid can stimulate the activity and the rate of activation of CalpA, but not CalpB. Calpain A modulates Toll responses by limited Cactus/IkappaB proteolysis. CalpB directly interacts with talin, an important component of the focal adhesion complex, and functions as an important modulator in border cell migration within egg chambers, which may act via the digestion of talin. CalpB can be phosphorylated by cAMP-dependent protein kinase (protein kinase A, PKA; EC 2.7.11.11) at Ser240 and Ser845, as well as by mitogen-activated protein kinase (ERK1 and ERK2; EC 2.7.11.24) at Thr747. The activation of the ERK pathway by extracellular signals results in the phosphorylation and activation of calpain B. In Schneider cells (S2), calpain B was mainly in the cytoplasm and upon a rise in Ca2+ the enzyme adhered to intracellular membranes.

Pssm-ID: 320071 [Multi-domain] Cd Length: 167 Bit Score: 36.80 E-value: 3.59e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183 102 DVDGNGTIDYIEFvtatmhqHKLERDEHLYK-AFQYFDKDHSGFITRDELETAMKEYGMGDDATIREIISEVDTDNDGRI 180
Cdd:cd16196    51 DVDRSGKLGFEEF-------KKLWEDLRSWKrVFKLFDTDGSGSFSSFELRNALNSAGFRLSNATLNALVLRYSNKDGRI 123


                  ....*
gi 2526894183 181 NYEEF 185
Cdd:cd16196   124 SFDDF 128

serine/threonine protein phosphatase 2A regulatory subunit B" alpha and beta subunits, and similar proteins; Heterotrimeric serine/threonine protein phosphatase 2A (PP2A) consists of scaffolding (A), catalytic (C), and variable (B, B', and B") subunits. The variable subunits dictate subcellular localization and substrate specificity of the PP2A holoenzyme. These B-family regulatory subunits play various roles including regulation of cytoskeletal assembly, neuronal differentiation, mitogen-activated protein kinase signaling, and apoptosis. This subfamily includes protein phosphatase 2A regulatory subunit B'' subunits alpha and beta, encoded by PPP2R3A and PPP2R3B. It also includes subunit delta encoded by PPP2R3D in mouse. They contain two-domain elongated structures with two calcium EF-hands which mediate Ca2+-dependent changes in phosphatase activity.

Pssm-ID: 410337 Cd Length: 274 Bit Score: 37.14 E-value: 4.15e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  61 VFTNIDTDKSGTITYEELKTGlaRLGSRLSEAEVEQlmeaadvDGNGTIDYIEFvtatmhqhklerdEHLYKAFQYF--- 137
Cdd:cd21504    67 IFYSVNRSWSGRITLRELRRS--NLLQALLLLDEEE-------DINKVLRYFSY-------------EHFYVIYCKFwel 124

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 2526894183 138 DKDHSGFITRDELetamkeYGMGDDA----TIREIISEVDTDN----DGRINYEEFC 186
Cdd:cd21504   125 DTDHDLLIDKDDL------LRYGDHAlsprIVDRIFSGAVRRFksgkEGKMSYEDFV 175

EF-hand, calcium binding motif, found in calbindin (CB); CB, also termed calbindin D28, or D-28K, or avian-type vitamin D-dependent calcium-binding protein, is a unique intracellular calcium binding protein that functions as both a calcium sensor and buffer in eukaryotic cells, which undergoes a conformational change upon calcium binding and protects cells against insults of high intracellular calcium concentration. CB is highly expressed in brain and sensory neurons. It plays essential roles in neural functioning, altering synaptic interactions in the hippocampus, modulating calcium channel activity, calcium transients, and intrinsic neuronal firing activity. It prevents a neuronal death, as well as maintains and controls calcium homeostasis. CB also modulates the activity of proteins participating in the development of neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, and bipolar disorder. Moreover, CB interacts with Ran-binding protein M, a protein known to involve in microtubule function. It also interacts with alkaline phosphatase and myo-inositol monophosphatase, as well as caspase 3, an enzyme that plays an important role in the regulation of apoptosis. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions with high affinity.

Pssm-ID: 320076 [Multi-domain] Cd Length: 243 Bit Score: 37.13 E-value: 4.19e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  61 VFTNIDTDKSGTITYEELKTGLARL-------GSRLSEaEVEQLMEAADVDGNGTIDYIEFVTAT--------MHQHKLE 125
Cdd:cd16176     4 IWHHYDNDGNGYIEGKELQSFIQELqqarkkaGLELSD-QMKAFVDQYGQSTDGKIGIVELAQILpteenfllFFRQQLK 82

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2526894183 126 RDEHLYKAFQYFDKDHSGFITRDELETAMKEYGMGDDATIRE---------IISEVDTDNDGRINYEEFCTMM 189
Cdd:cd16176    83 SSEEFMQTWRKYDADHSGFIEADELKSFLKDLLKKANKPFDEskleeythtMLKMFDSNNDGKLGLTEMARLL 155

Penta-EF hand, calcium binding motifs, found in Drosophila melanogaster calpain-A (CalpA), calpain-B (CalpB), and similar proteins; The family contains two calpains that have been found in Drosophila, CalpA and CalpB. CalpA, also termed calcium-activated neutral proteinase A (CANP A), or calpain-A catalytic subunit, is a Drosophila calpain homolog specifically expressed in a few neurons in the central nervous system, in scattered endocrine cells in the midgut, and in blood cells. CalpB, also termed calcium-activated neutral proteinase B (CANP B), contains calpain-B catalytic subunit 1 and calpain-B catalytic subunit 2. Both CalpA and CalpB are closely related to that of vertebrate calpains, and they share similar domain architecture, which consists of four domains: the N-terminal domain I, the catalytic domain II carrying the three active site residues, Cys, His and Asn, the Ca2+-regulated phospholipid-binding domain III, and penta-EF-hand Ca2+-binding domain IV. Besides, CalpA and CalpB display some distinguishing structural features that are not found in mammalian typical calpains. CalpA harbors a 76 amino acid long hydrophobic stretch inserted in domain IV, which may be involved in membrane attachment of this enzyme. CalpB has an unusually long N-terminal tail of 224 amino acids, which belongs to the class of intrinsically unstructured proteins (IUP) and may become ordered upon binding to target protein(s). Moreover, they do not need small regulatory subunits for their catalytic activity, and their proteolytic function is not regulated by an intrinsic inhibitor as the Drosophila genome contains neither regulatory subunit nor calpastatin orthologs. As a result, they may exist as a monomer or perhaps as a homo- or heterodimer together with a second large subunit. Furthermore, both CalpA and CalpB are dispensable for viability and fertility and do not share vital functions during Drosophila development. Phosphatidylinositol 4,5-diphosphate, phosphatidylinositol 4-monophosphate, phosphatidylinositol, and phosphatidic acid can stimulate the activity and the rate of activation of CalpA, but not CalpB. Calpain A modulates Toll responses by limited Cactus/IkappaB proteolysis. CalpB directly interacts with talin, an important component of the focal adhesion complex, and functions as an important modulator in border cell migration within egg chambers, which may act via the digestion of talin. CalpB can be phosphorylated by cAMP-dependent protein kinase (protein kinase A, PKA; EC 2.7.11.11) at Ser240 and Ser845, as well as by mitogen-activated protein kinase (ERK1 and ERK2; EC 2.7.11.24) at Thr747. The activation of the ERK pathway by extracellular signals results in the phosphorylation and activation of calpain B. In Schneider cells (S2), calpain B was mainly in the cytoplasm and upon a rise in Ca2+ the enzyme adhered to intracellular membranes.

Pssm-ID: 320071 [Multi-domain] Cd Length: 167 Bit Score: 36.41 E-value: 4.83e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  50 LSEEEIKGL-------KAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQL-MEAADVDGNgtIDYIEFVTATMhq 121
Cdd:cd16196    58 LGFEEFKKLwedlrswKRVFKLFDTDGSGSFSSFELRNALNSAGFRLSNATLNALvLRYSNKDGR--ISFDDFIMCAV-- 133

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 2526894183 122 hKLERdehLYKAFQYFDKDHSGFIT--RDE-LETAM 154
Cdd:cd16196   134 -KLKT---MFEIFKEKDPRGGGRATfnLDEfLESTM 165

EF hand; The EF-hands can be divided into two classes: signalling proteins and buffering/transport proteins. The first group is the largest and includes the most well-known members of the family such as calmodulin, troponin C and S100B. These proteins typically undergo a calcium-dependent conformational change which opens a target binding site. The latter group is represented by calbindin D9k and do not undergo calcium dependent conformational changes.

Pssm-ID: 425435 [Multi-domain] Cd Length: 29 Bit Score: 33.53 E-value: 4.85e-03

                          10        20
                  ....*....|....*....|....*...
gi 2526894183  58 LKAVFTNIDTDKSGTITYEELKTGLARL 85
Cdd:pfam00036   2 LKEIFRLFDKDGDGKIDFEEFKELLKKL 29

EF-hand motif found in Saccharomyces cerevisiae phospholipase C-1 (ScPlc1p) and similar proteins; This family represents a group of putative phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11) encoded by PLC1 genes from yeasts, which are homologs of the delta isoforms of mammalian PI-PLC in terms of overall sequence similarity and domain organization. Mammalian PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. The prototype of this family is protein Plc1p (also termed 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase 1) encoded by PLC1 genes from Saccharomyces cerevisiae. ScPlc1p contains both highly conserved X- and Y- regions of PLC catalytic core domain, as well as a presumptive EF-hand like calcium binding motif. Experiments show that ScPlc1p displays calcium dependent catalytic properties with high similarity to those of the mammalian PLCs, and plays multiple roles in modulating the membrane/protein interactions in filamentation control. CaPlc1p encoded by CAPLC1 from the closely related yeast Candida albicans, an orthologue of S. cerevisiae Plc1p, is also included in this group. Like SCPlc1p, CaPlc1p has conserved presumptive catalytic domain, shows PLC activity when expressed in E. coli, and is involved in multiple cellular processes. There are two other gene copies of CAPLC1 in C. albicans, CAPLC2 (also named as PIPLC) and CAPLC3. Experiments show CaPlc1p is the only enzyme in C. albicans which functions as PLC. The biological functions of CAPLC2 and CAPLC3 gene products must be clearly different from CaPlc1p, but their exact roles remain unclear. Moreover, CAPLC2 and CAPLC3 gene products are more similar to extracellular bacterial PI-PLC than to the eukaryotic PI-PLC, and they are not included in this subfamily.

Pssm-ID: 320037 [Multi-domain] Cd Length: 142 Bit Score: 35.69 E-value: 5.13e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  68 DKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIEFvtatmhQH--KL--ERDE--HLYKAFQyfdKDH 141
Cdd:cd16207    14 DGDERLDFEDVEKLCRRLHINCSESYLRELFDKADTDKKGYLNFEEF------QEfvKLlkRRKDikAIFKQLT---KPG 84

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 2526894183 142 SGFITRDELETAMKEYGM--GDDATIREI----ISEVDTDNDGRINYEEF 185
Cdd:cd16207    85 SDGLTLEEFLKFLRDVQKedVDRETWEKIfekfARRIDDSDSLTMTLEGF 134

EF-hand, calcium binding motif; EF-hands are calcium-binding motifs that occur at least in pairs. Links between disease states and genes encoding EF-hands, particularly the S100 subclass, are emerging. Each motif consists of a 12 residue loop flanked on either side by a 12 residue alpha-helix. EF-hands undergo a conformational change unpon binding calcium ions.

Pssm-ID: 197492 [Multi-domain] Cd Length: 29 Bit Score: 33.12 E-value: 6.06e-03

                           10        20
                   ....*....|....*....|....*
gi 2526894183  132 KAFQYFDKDHSGFITRDELETAMKE 156
Cdd:smart00054   4 EAFRLFDKDGDGKIDFEEFKDLLKA 28

phosphatidylserine decarboxylase

Pssm-ID: 215520 [Multi-domain] Cd Length: 644 Bit Score: 36.76 E-value: 6.58e-03

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2526894183  47 AENLSEEEIKGLKAVFTNIDTDKSGTITYEELKTGLARLGSRLSEAEVEQLMEAADVDGNGTIDYIE 113
Cdd:PLN02964  170 IEDPVETERSFARRILAIVDYDEDGQLSFSEFSDLIKAFGNLVAANKKEELFKAADLNGDGVVTIDE 236

EF-hand, calcium binding motif, found in Drosophila melanogaster calbindin-32 (CBN) and similar proteins; CBN, the product of the cbn gene, is a Drosophila homolog to vertebrate neuronal six EF-hand calcium binding proteins. It is expressed through most of ontogenesis with a selective distribution in the nervous system and in a few small adult thoracic muscles. Its precise biological role remains unclear. CBN contains six EF-hand motifs, but some of them may not bind calcium ions due to the lack of key residues.

Pssm-ID: 320079 [Multi-domain] Cd Length: 261 Bit Score: 36.23 E-value: 6.60e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  66 DTDKSGTITYEELKTGLARL---GSRLSEAEVEQLMEAADV-------DGNGTIDYIEFV------------TATMHQHK 123
Cdd:cd16179   105 DKDNSGYIEADELKNFLKHLlkeAKRDNDVSEDKLIEYTDTilqlfdrNKDGKLQLSEMArllpvkenflcrPIFKGAGK 184

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2526894183 124 LERDEhLYKAFQYFDKDHSGFITRDEL--------ETAMKEYGMGDDATIREII-SEVDTDNDGRINYEEFcTMM 189
Cdd:cd16179   185 LTRED-IDRVFALYDRDNNGTIENEELtgflkdllELVQEDYDEQDLEEFKEIIlRGWDFNNDGKISRKEL-TML 257

EF-hand, calcium binding motif; EF-hands are calcium-binding motifs that occur at least in pairs. Links between disease states and genes encoding EF-hands, particularly the S100 subclass, are emerging. Each motif consists of a 12 residue loop flanked on either side by a 12 residue alpha-helix. EF-hands undergo a conformational change unpon binding calcium ions.

Pssm-ID: 197492 [Multi-domain] Cd Length: 29 Bit Score: 33.12 E-value: 6.63e-03

                           10        20
                   ....*....|....*....|....*...
gi 2526894183   58 LKAVFTNIDTDKSGTITYEELKTGLARL 85
Cdd:smart00054   2 LKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

EF-hand, calcium binding motif, found in reticulocalbin-2 (RCN2) mainly from protostomes; This family corresponds to a group of uncharacterized RCN2-like proteins, which are mainly found in protostomes. Although their biological function remains unclear, they show high sequence similarity with RCN2 (also known as E6BP or TCBP-49), which is an endoplasmic reticulum resident low-affinity Ca2+-binding protein that has been implicated in immunity, redox homeostasis, cell cycle regulation and coagulation. Members in this family contain six copies of the EF-hand Ca2+-binding motif, but may lack a C-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide that is required for retention of RCN2 in the endoplasmic reticulum (ER).

Pssm-ID: 320025 [Multi-domain] Cd Length: 263 Bit Score: 36.53 E-value: 7.01e-03

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2526894183  59 KAVFTNIDTDKSGTITYEELKTGLA-RLGSRLSEAEVEQLMEAADVDGNGTIDYIEFVTATMHQH-----KLERDEHLYk 132
Cdd:cd16227   125 KEMFEAADLNKDGKLDKTEFSAFQHpEEYPHMHPVLIEQTLRDKDKDNDGFISFQEFLGDRAGHEdkewlLVEKDRFDE- 203

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2526894183 133 afqYFDKDHSGFITRDEL---------ETAMKEygmgddatIREIISEVDTDNDGRINYEE 184
Cdd:cd16227   204 ---DYDKDGDGKLDGEEIlswlvpdneEIAEEE--------VDHLFASADDDHDDRLSFDE 253

Cytoskeletal-regulatory complex EF hand; This is an efhand family from the N-terminal of actin cytoskeleton-regulatory complex END3 and similar proteins from fungi and closely related species.

Pssm-ID: 289529 Cd Length: 104 Bit Score: 34.66 E-value: 9.24e-03

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2526894183  50 LSEEEIK-------GLKAVFTNIDTDKSGTItyeeLKTglarlgSRLSEAEVEQLMEAADVDGNGTIDYIEFVTA 117
Cdd:pfam12763   4 LEEWEIKkyweifsGLKPENNKLTGDQVSPV----LKN------SRLPDDQLAKIWDLADIDSDGKLDFEEFCIA 68

EF-hand, calcium binding motif; A diverse superfamily of calcium sensors and calcium signal modulators; most examples in this alignment model have 2 active canonical EF hands. Ca2+ binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers.

Pssm-ID: 238008 [Multi-domain] Cd Length: 63 Bit Score: 33.29 E-value: 9.69e-03

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 2526894183  42 ALKVIAENLSEEEIKglkAVFTNIDTDKSGTITYEELKTGLA 83
Cdd:cd00051    25 ALKSLGEGLSEEEID---EMIREVDKDGDGKIDFEEFLELMA 63