NCBI Conserved Domain Search

calmodulin; Provisional

Pssm-ID: 185504 [Multi-domain] Cd Length: 149 Bit Score: 149.14 E-value: 9.56e-47

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617    12 LSEEMIAEFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQMKEdakGK 91
Cdd:PTZ00184   5 LTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKMKD---TD 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 4507617    92 SEEELAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 156
Cdd:PTZ00184  82 SEEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMM 146

centrin; Provisional

Pssm-ID: 185503 [Multi-domain] Cd Length: 158 Bit Score: 111.70 E-value: 5.73e-32

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617     5 QAEARSYLSEEMIAEFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQM 84
Cdd:PTZ00183   4 RRSERPGLTEDQKKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMTKKL 83

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 4507617    85 kedAKGKSEEELAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 156
Cdd:PTZ00183  84 ---GERDPREEILKAFRLFDDDKTGKISLKNLKRVAKELGETITDEELQEMIDEADRNGDGEISEEEFYRIM 152

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

Pssm-ID: 444056 [Multi-domain] Cd Length: 137 Bit Score: 82.15 E-value: 1.27e-20

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   14 EEMIAEFKAAFDMFDADGGGDISVKELGTVMRMLgqtptkeeLDAIIEEVDEDGSGTIDFEEFLVMMVRQMKEDAkgksE 93
Cdd:COG5126   1 DLQRRKLDRRFDLLDADGDGVLERDDFEALFRRL--------WATLFSEADTDGDGRISREEFVAGMESLFEATV----E 68

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 4507617   94 EELAECFRIFDRNADGYIDPEELAEIFRASGehVTDEEIESLMKDGDKNNDGRIDFDEFLKMMEG 158
Cdd:COG5126  69 PFARAAFDLLDTDGDGKISADEFRRLLTALG--VSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

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: 73.74 E-value: 3.46e-18

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 4507617   95 ELAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 156
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

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: 72.97 E-value: 6.00e-18

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 4507617   19 EFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMM 80
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

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: 75.26 E-value: 8.30e-18

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   19 EFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEE-LDAIIEEVDEDGSGTIDFEEF--LVMMVRQMKEdakgkseee 95
Cdd:cd16180   1 ELRRIFQAVDRDRSGRISAKELQRALSNGDWTPFSIEtVRLMINMFDRDRSGTINFDEFvgLWKYIQDWRR--------- 71

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 4507617   96 laeCFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 156
Cdd:cd16180  72 ---LFRRFDRDRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDFVEAC 129

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: 67.62 E-value: 6.63e-15

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   19 EFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVM--MVRQMKEdakgkseeel 96
Cdd:cd16185   1 ELRQWFRAVDRDRSGSIDVNELQKALAGGGLLFSLATAEKLIRMFDRDGNGTIDFEEFAALhqFLSNMQN---------- 70

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 4507617   97 aeCFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKM 155
Cdd:cd16185  71 --GFEQRDTSRSGRLDANEVHEALAASGFQLDPPAFQALFRKFDPDRGGSLGFDDYIEL 127

EF-hand domain pair;

Pssm-ID: 463900 [Multi-domain] Cd Length: 67 Bit Score: 63.04 E-value: 4.43e-14

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 4507617     93 EEELAECFRIFDRNADGYIDPEELAEIFRAS--GEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 156
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLeeGEPLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

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: 64.58 E-value: 9.96e-14

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   24 FDMFDADGGGDISVKELGTVMRMLGQTPTKEE-LDAIIEEVDEDGSGTIDFEEFLvmmvrqmkedAKGKSEEELAECFRI 102
Cdd:cd16183   6 FQRVDKDRSGQISATELQQALSNGTWTPFNPEtVRLMIGMFDRDNSGTINFQEFA----------ALWKYITDWQNCFRS 75

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 4507617  103 FDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEF 152
Cdd:cd16183  76 FDRDNSGNIDKNELKQALTSFGYRLSDQFYDILVRKFDRQGRGTIAFDDF 125

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

Pssm-ID: 444056 [Multi-domain] Cd Length: 137 Bit Score: 62.50 E-value: 4.54e-13

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617    9 RSYLSEEMIAEFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMvrqmkeDA 88
Cdd:COG5126  24 RDDFEALFRRLWATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEFRRLL------TA 97

                        90       100       110
                ....*....|....*....|....*....|...
gi 4507617   89 KGKSEEELAECFRIFDRNADGYIDPEELAEIFR 121
Cdd:COG5126  98 LGVSEEEADELFARLDTDGDGKISFEEFVAAVR 130

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: 60.76 E-value: 2.08e-12

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   20 FKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQMkedakgkSEEELAEC 99
Cdd:cd15898   2 LRRQWIKADKDGDGKLSLKEIKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELYKSLT-------ERPELEPI 74

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 4507617  100 FRIFDRNADGYIDPEELAEIFRA-SGEHVTDEEIESLMKD-GDKNNDGRIDFDEFLKMM 156
Cdd:cd15898  75 FKKYAGTNRDYMTLEEFIRFLREeQGENVSEEECEELIEKyEPERENRQLSFEGFTNFL 133

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: 56.77 E-value: 2.63e-11

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   69 GTIDFEEFLVMMvrqmkeDAKGKSEEELAECFRIFDRNADGYIDPEELAEI---FRASGEHVTDEEIESLMKDGDKNNDG 145
Cdd:cd16251  15 GSFNYKKFFEHV------GLKQKSEDQIKKVFQILDKDKSGFIEEEELKYIlkgFSIAGRDLTDEETKALLAAGDTDGDG 88

                        90
                ....*....|...
gi 4507617  146 RIDFDEFLKMMEG 158
Cdd:cd16251  89 KIGVEEFATLVAG 101

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: 56.76 E-value: 2.75e-11

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 4507617   89 KGKSEEELAECFRIFDRNADGYIDPEELAEI---FRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 156
Cdd:cd16254  29 KKKSADDVKKVFHILDKDKSGFIEEDELKFVlkgFSPDGRDLSDKETKALLAAGDKDGDGKIGIDEFATLV 99

calmodulin; Provisional

Pssm-ID: 185504 [Multi-domain] Cd Length: 149 Bit Score: 55.54 E-value: 2.14e-10

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 4507617    19 EFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQ 83
Cdd:PTZ00184  85 EIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMMSK 149

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: 54.54 E-value: 8.11e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   26 MFD--ADGGGDISVKELGTVMR--MLGQTPTKEELD-----AIIEEVDEDGSGTIDFEEFLVMMvrqmkedakgKSEEEL 96
Cdd:cd16182   5 LFEklAGEDEEIDAVELQKLLNasLLKDMPKFDGFSletcrSLIALMDTNGSGRLDLEEFKTLW----------SDLKKW 74

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 4507617   97 AECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKD-GDKNndGRIDFDEFL 153
Cdd:cd16182  75 QAIFKKFDTDRSGTLSSYELRKALESAGFHLSNKVLQALVLRyADST--GRITFEDFV 130

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

Pssm-ID: 444056 [Multi-domain] Cd Length: 137 Bit Score: 52.49 E-value: 3.10e-09

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 4507617   14 EEMIAEFKAAFDMFDADGGGDISVKELGTVMRMLGqtPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQMKEDA 88
Cdd:COG5126  65 ATVEPFARAAFDLLDTDGDGKISADEFRRLLTALG--VSEEEADELFARLDTDGDGKISFEEFVAAVRDYYTPDA 137

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: 50.88 E-value: 4.84e-09

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 4507617   90 GKSEEELAECFRIFDRNADGYIDPEELA---EIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKM 155
Cdd:cd16255  30 KKSADDVKKVFEIIDQDKSGFIEEEELKlflQNFSSGARELTDAETKAFLKAGDSDGDGKIGVEEFQAL 98

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: 52.74 E-value: 7.36e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   24 FDMFDADGGGDISVKELGTVMRMLGQTPTKEELDA---------IIEEVDEDGSGTIDFEEFLVMMV------RQMKEDA 88
Cdd:cd15902   5 WMHFDADGNGYIEGKELDSFLRELLKALNGKDKTDdevaekkkeFMEKYDENEDGKIEIRELANILPteenflLLFRREQ 84

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 4507617   89 KGKSEEELAECFRIFDRNADGYIDPEELAEIFR--------ASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 156
Cdd:cd15902  85 PLISSVEFMKIWRKYDTDGSGFIEAKELKGFLKdlllknkkHVSPPKLDEYTKLILKEFDANKDGKLELDEMAKLL 160

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: 51.66 E-value: 8.03e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   29 ADGGGDISVKELGTVMRMLGQTPTK-----EELDAIIEEVDEDGSGTIDFEEF--LVMMVRQMKEDakgkseeelaecFR 101
Cdd:cd15897  10 AGDDGEISATELQQALSNVGWTHFDlgfslETCRSMIAMMDRDHSGKLNFSEFkgLWNYIKAWQEI------------FR 77

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 4507617  102 IFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNdGRIDFDEFL 153
Cdd:cd15897  78 TYDTDGSGTIDSNELRQALSGAGYRLSEQTYDIIIRRYDRGR-GNIDFDDFI 128

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: 51.50 E-value: 9.29e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   24 FDMFDADGGGDISVKEL-GTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEF--LVMMVRQMKEdakgkseeelaeCF 100
Cdd:cd16184   6 FQAVDRDRSGKISAKELqQALVNGNWSHFNDETCRLMIGMFDKDKSGTIDIYEFqaLWNYIQQWKQ------------VF 73

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 4507617  101 RIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEF 152
Cdd:cd16184  74 QQFDRDRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRARRSLTLDQF 125

XopAW family type III secretion system calcium-binding effector;

Pssm-ID: 469301 [Multi-domain] Cd Length: 227 Bit Score: 52.38 E-value: 1.05e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617    24 FDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMV----RQMKEDAKGKSEEELAEc 99
Cdd:NF041410  33 FAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAPppppPPDQAPSTELADDLLSA- 111

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 4507617   100 friFDRNADGYIDPEELAEIFRASGehvTDEEIESLMKDGDKNNDGRIDFDEF 152
Cdd:NF041410 112 ---LDTDGDGSISSDELSAGLTSAG---SSADSSQLFSALDSDGDGSVSSDEL 158

EF-hand domain pair;

Pssm-ID: 463900 [Multi-domain] Cd Length: 67 Bit Score: 48.40 E-value: 2.12e-08

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 4507617     21 KAAFDMFDADGGGDISVKELGTVMRML--GQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMM 80
Cdd:pfam13499   5 KEAFKLLDSDGDGYLDVEELKKLLRKLeeGEPLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

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: 50.06 E-value: 3.23e-08

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   27 FDADGG--GDISVKELGTVMRMLG-----QTPTKEELDAIIEEVDEDGSGTIDFEEF--LVMMVRQMKEDakgkseeela 97
Cdd:cd16181   6 FSAVAGqdGQIDADELQRCLTQSGisgnyQPFSLETCRLMIAMLDRDHSGKMGFNEFkeLWAALNQWKTT---------- 75

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 4507617   98 ecFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNndGRIDFDEFL 153
Cdd:cd16181  76 --FMQYDRDRSGTVEPQELQQAIRSFGYNLSPQALNVIVKRYSKN--GRITFDDFV 127

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: 48.82 E-value: 6.88e-08

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   56 LDAIIEEVDEDGSGTIDFEEflvmMVRQMKEDAKGKSEEELAECFRIFDRNADGYIDPEELAEIFRasgEHVTDEEIESL 135
Cdd:cd15898   2 LRRQWIKADKDGDGKLSLKE----IKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELYK---SLTERPELEPI 74

                        90       100
                ....*....|....*....|....*
gi 4507617  136 MKDGDKNNDGRIDFDEFLKMMEGVQ 160
Cdd:cd15898  75 FKKYAGTNRDYMTLEEFIRFLREEQ 99

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: 47.99 E-value: 1.31e-07

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   20 FKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVD----------------EDGSGTIDFEEFLVMMVRQ 83
Cdd:cd15900   2 FEIAFKMFDLDGDGELDKEEFNKVQSIIRSQTSVGQRHRDHTNGEstklgmnstlaryffgKDGKQKLSIEKFLEFQENL 81

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 4507617   84 MKEdakgksEEELAECFRIFdRNADGYIDPEELAEIFRAS-GEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 156
Cdd:cd15900  82 QEE------IDDVDTALTFY-HLAGASIDRKTFKRAAKVVaGVELSDHVVDVVFTIFDEDGDGILSHKEFISVM 148

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: 48.98 E-value: 1.58e-07

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   59 IIEEVDEDGSGTIDFEEFLVMMVR-QMKEDAKGKSEEELAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMK 137
Cdd:cd15899 165 TLEDLDKNGDGFISLEEFISDPYSaDENEEEPEWVKVEKERFVELRDKDKDGKLDGEELLSWVDPSNQEIALEEAKHLIA 244

                        90
                ....*....|....*..
gi 4507617  138 DGDKNNDGRIDFDEFLK 154
Cdd:cd15899 245 ESDENKDGKLSPEEILD 261

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: 46.40 E-value: 2.28e-07

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   89 KGKSEEELAECFRIFDRNADGYIDPEELAEI---FRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKM 155
Cdd:cd16253  29 SKKSPADIKKVFNILDQDKSGFIEEEELKLFlknFSDGARVLSDKETKNFLAAGDSDGDGKIGVDEFKSM 98

XopAW family type III secretion system calcium-binding effector;

Pssm-ID: 469301 [Multi-domain] Cd Length: 227 Bit Score: 46.60 E-value: 1.04e-06

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617    21 KAAFDMFDADGGGDISVKELGTVMRM----LGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMvrqmkedAKGKSEEEL 96
Cdd:NF041410  66 SELFSDLDSDGDGSLSSDELAAAAPPppppPDQAPSTELADDLLSALDTDGDGSISSDELSAGL-------TSAGSSADS 138

                         90       100
                 ....*....|....*....|.
gi 4507617    97 AECFRIFDRNADGYIDPEELA 117
Cdd:NF041410 139 SQLFSALDSDGDGSVSSDELA 159

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: 45.71 E-value: 1.13e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   17 IAEFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFL---VMMVRqmkedakgkse 93
Cdd:cd16183  66 ITDWQNCFRSFDRDNSGNIDKNELKQALTSFGYRLSDQFYDILVRKFDRQGRGTIAFDDFIqccVVLQT----------- 134

                        90
                ....*....|....*....
gi 4507617   94 eeLAECFRIFDRNADGYID 112
Cdd:cd16183 135 --LTDSFRRYDTDQDGWIQ 151

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: 46.76 E-value: 1.16e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   27 FDADGGGDISVKELGTVMRMLGQTPTK------EELDAIIEEVDEDGSGTIDF----------EEFLVMMVRQMKedakg 90
Cdd:cd16176   8 YDNDGNGYIEGKELQSFIQELQQARKKaglelsDQMKAFVDQYGQSTDGKIGIvelaqilpteENFLLFFRQQLK----- 82

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 4507617   91 kSEEELAECFRIFDRNADGYIDPEELAEIF--------RASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 156
Cdd:cd16176  83 -SSEEFMQTWRKYDADHSGFIEADELKSFLkdllkkanKPFDESKLEEYTHTMLKMFDSNNDGKLGLTEMARLL 155

EF-hand domain pair;

Pssm-ID: 404678 [Multi-domain] Cd Length: 54 Bit Score: 43.07 E-value: 1.59e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 4507617    108 DGYIDPEELAEIFRASG-EHVTDEEIESLMKDGDKNNDGRIDFDEFLKMME 157
Cdd:pfam13833   2 KGVITREELKRALALLGlKDLSEDEVDILFREFDTDGDGYISFDEFCVLLE 52

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: 46.24 E-value: 1.61e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   20 FKAAFDMFDADGGGDISVKELGTVMRMLGQ------TPTKEELDAIIEEV----DEDGSGTIDFEEFLVMMVRQ------ 83
Cdd:cd16178   1 FAEIWQHFDADESGYIEGKELDNFFKDLLKklgtkdTISADEVQDVKECFmsayDVTGDGRIQIQELANIILPDdenfll 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   84 -MKEDAKGKSEEELAECFRIFDRNADGYIDPEEL----AEIFRASGEHVTDEEIE----SLMKDGDKNNDGRIDFDEFLK 154
Cdd:cd16178  81 fFRREEPLDSSVEFMRIWRKYDADSSGYISAAELknflRDLFLQHKKVITEDKLDeytdTMMKIFDKNKDGRLDLNDMAR 160


                ..
gi 4507617  155 MM 156
Cdd:cd16178 161 IL 162

EF-hand domain pair;

Pssm-ID: 404678 [Multi-domain] Cd Length: 54 Bit Score: 42.69 E-value: 2.07e-06

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 4507617     31 GGGDISVKELGTVMRMLG-QTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQ 83
Cdd:pfam13833   1 EKGVITREELKRALALLGlKDLSEDEVDILFREFDTDGDGYISFDEFCVLLERR 54

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: 45.81 E-value: 2.20e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617    9 RSYLSEEMIAEFKAAFDMFDADGGGDISVKELGTVMRML--------GQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMM 80
Cdd:cd15902  81 RREQPLISSVEFMKIWRKYDTDGSGFIEAKELKGFLKDLllknkkhvSPPKLDEYTKLILKEFDANKDGKLELDEMAKLL 160

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   81 VRQ----MKEDAKGKSE---EELAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEE--------IESLMKDGDKNNDG 145
Cdd:cd15902 161 PVQenflLKFQILGAMDltkEDFEKVFEHYDKDNNGVIEGNELDALLKDLLEKNKADIdkpdlenfRDAILRACDKNKDG 240


                ....*.
gi 4507617  146 RIDFDE 151
Cdd:cd15902 241 KIQKTE 246

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: 45.12 E-value: 3.56e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   60 IEEVDEDGSGTIDFEEFLVMMVR--QMKEDAKGKSEEELaECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMK 137
Cdd:cd16224 167 LEEHDKDGDGFISLEEFLGDYRKdpTANEDPEWIIVEKD-RFVNDYDKDNDGKLDPQELLPWVVPNNYGIAQEEALHLID 245

                        90       100
                ....*....|....*....|
gi 4507617  138 DGDKNNDGRIDFDEFLKMME 157
Cdd:cd16224 246 EMDLNGDGRLSEEEILENQD 265

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: 44.44 E-value: 4.04e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   17 IAEFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFL-VMMVRQMkedakgkseee 95
Cdd:cd16180  66 IQDWRRLFRRFDRDRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDFVeACVTLKR----------- 134

                        90
                ....*....|....*.
gi 4507617   96 LAECFRIFDRNADGYI 111
Cdd:cd16180 135 LTDAFRKYDTNRTGYA 150

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: 42.90 E-value: 6.55e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   69 GTIDFEEFLVMMvrqMKEDAKGKSEEELAECFRIFDRNADGYIDPEELAEIFRASGEH-----VTDEEIESLMKDGDKNN 143
Cdd:cd16252  15 GSFNYSKFFEYM---QKFQTSEQQEEAIRKAFQMLDKDKSGFIEWNEIKYILSTVPSSmpvapLSDEEAEAMIQAADTDG 91

                        90
                ....*....|....*
gi 4507617  144 DGRIDFDEFLKMMEG 158
Cdd:cd16252  92 DGRIDFQEFSDMVKK 106

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: 44.23 E-value: 7.09e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   55 ELDAIIEEVDEDGSGTIDFEEFLVMMVRQMKEDAKgKSEEELAEcfRIFDRNADGYIDPEELAEIFRASGEHVTDEEIES 134
Cdd:cd16227 160 LIEQTLRDKDKDNDGFISFQEFLGDRAGHEDKEWL-LVEKDRFD--EDYDKDGDGKLDGEEILSWLVPDNEEIAEEEVDH 236

                        90
                ....*....|....*....
gi 4507617  135 LMKDGDKNNDGRIDFDEFL 153
Cdd:cd16227 237 LFASADDDHDDRLSFDEIL 255

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: 43.34 E-value: 1.48e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   24 FDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQMKEDAK-GKSEEELAEC--- 99
Cdd:cd16226  41 VDKIDKNGDGFVTEEELKDWIKYVQKKYIREDVDRQWKEYDPNKDGKLSWEEYKKATYGFLDDEEEdDDLHESYKKMirr 120

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 4507617  100 ----FRIFDRNADGYIDPEELAE-IFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMM 156
Cdd:cd16226 121 derrWKAADQDGDGKLTKEEFTAfLHPEEFPHMRDIVVQETLEDIDKNKDGFISLEEYIGDM 182

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: 41.75 E-value: 1.57e-05

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 4507617   13 SEEMIAEFKAAFDMFDADGGGDISVKE----LGTVMRMLGQTP-TKEELDAIIEEVDEDGSGTIDFEEFLVM 79
Cdd:cd16252  32 SEQQEEAIRKAFQMLDKDKSGFIEWNEikyiLSTVPSSMPVAPlSDEEAEAMIQAADTDGDGRIDFQEFSDM 103

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: 42.96 E-value: 1.94e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   60 IEEVDEDGSGTIDFEEFLVMMVRQ---MKEDAKGKSEEELAECFRifDRNADGYIDPEELAEIFRASGEHVTDEEIESLM 136
Cdd:cd16226 162 LEDIDKNKDGFISLEEYIGDMYRDddeEEDPDWVKSEREQFKEFR--DKNKDGKMDREEVKDWILPEDYDHAEAEAKHLI 239

                        90
                ....*....|....*..
gi 4507617  137 KDGDKNNDGRIDFDEFL 153
Cdd:cd16226 240 YEADDDKDGKLTKEEIL 256

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: 39.51 E-value: 4.29e-05

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 4507617   98 ECFRIFDRNADGYIDPEELAEIFRASGEHVTD-EEIESLMkdgDKNNDGRIDFDEF 152
Cdd:cd00052   3 QIFRSLDPDGDGLISGDEARPFLGKSGLPRSVlAQIWDLA---DTDKDGKLDKEEF 55

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: 42.04 E-value: 4.71e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   14 EEMIAEFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMV-----RQMKEDA 88
Cdd:cd15899  31 EESKRRLGVIVSKMDVDKDGFISAKELHSWILESFKRHAMEESKEQFRAVDPDEDGHVSWDEYKNDTYgsvgdDEENVAD 110

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   89 KGKSEEELAEC-------FRIFDRNADGYIDPEE-LAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMMEGVQ 160
Cdd:cd15899 111 NIKEDEEYKKLllkdkkrFEAADQDGDLILTLEEfLAFLHPEESPYMLDFVIKETLEDLDKNGDGFISLEEFISDPYSAD 190

EF-hand domain pair;

Pssm-ID: 463900 [Multi-domain] Cd Length: 67 Bit Score: 38.39 E-value: 1.11e-04

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 4507617     61 EEVDEDGSGTIDFEEFLVMMvrQMKEDAKGKSEEELAECFRIFDRNADGYIDPEELAEIFR 121
Cdd:pfam13499   9 KLLDSDGDGYLDVEELKKLL--RKLEEGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

phosphatidylserine decarboxylase

Pssm-ID: 215520 [Multi-domain] Cd Length: 644 Bit Score: 41.38 E-value: 1.12e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 4507617   102 IFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDE 151
Cdd:PLN02964 187 IVDYDEDGQLSFSEFSDLIKAFGNLVAANKKEELFKAADLNGDGVVTIDE 236

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: 37.97 E-value: 1.69e-04

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 4507617   20 FKAAFDMFDADGGGDISVKELGTVMRMLGqTPtKEELDAIIEEVDEDGSGTIDFEEFLVMM 80
Cdd:cd00052   1 YDQIFRSLDPDGDGLISGDEARPFLGKSG-LP-RSVLAQIWDLADTDKDGKLDKEEFAIAM 59

N-terminal domain of Myosin essential light chain ELC; ELC is part of the apicomplexan membrane-associated protein complex called the glideosome, which is essential for parasite motility. The glideosome is composed of six proteins: myosin A (MyoA), essential light chain ELC, myosin light chain MLC1 (also called MTIP), and the glideosome-associated proteins GAP40, GAP45, and GAP50. MyoA is a Class XIV myosin implicated in gliding motility, as well as host cell and tissue invasion by parasites. ELC binds to the MyoA neck region adjacent to the MLC1-binding site, and both myosin light chains co-located to the glideosome. Although ELCs bind to a conserved MyoA sequence, P. falciparum ELC adopts a distinct structure in the free and MyoA-bound state. Therefore ELCs enhance MyoA performance by inducing alpha helical structure formation in MyoA and thus stiffening its lever arm. It has been shown that disruption of MyoA, MLC1, or ELC have dramatic effects on parasite motility but do not affect parasite shape or replication. The ELC N-terminal domain is part of the EF-hand calcium binding motif superfamily. Calcium binding has no effect on the structure of ELCs.

Pssm-ID: 439385 [Multi-domain] Cd Length: 66 Bit Score: 37.71 E-value: 1.82e-04

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....
gi 4507617   92 SEEELAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESL 135
Cdd:cd22949   1 MEEKFREAFILFDRDGDGELTMYEAVLAMRSCGIPLTNDEKDAL 44

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: 40.09 E-value: 1.98e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   19 EFKAAFDMFDADGGGDISVKELGTVMRML---GQTPTKEELDAIIEEV-------DEDGSGTIDFEEFLVMM-------V 81
Cdd:cd16179  96 EFMKVWREYDKDNSGYIEADELKNFLKHLlkeAKRDNDVSEDKLIEYTdtilqlfDRNKDGKLQLSEMARLLpvkenflC 175

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   82 RQMKEDAKGKSEEELAECFRIFDRNADGYIDPEELA----EIFRASGEHVTDEEI----ESLMKDGDKNNDGRIDFDEfL 153
Cdd:cd16179 176 RPIFKGAGKLTREDIDRVFALYDRDNNGTIENEELTgflkDLLELVQEDYDEQDLeefkEIILRGWDFNNDGKISRKE-L 254


                ...
gi 4507617  154 KMM 156
Cdd:cd16179 255 TML 257

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: 38.41 E-value: 2.24e-04

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 4507617      92 SEEELA---ECFRIFDRNADGYIDPEELAEIFRASGehVTDEEIESLMKDGDKNNDGRIDFDEF 152
Cdd:smart00027   5 SPEDKAkyeQIFRSLDKNQDGTVTGAQAKPILLKSG--LPQTLLAKIWNLADIDNDGELDKDEF 66

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: 39.87 E-value: 2.29e-04

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 4507617   92 SEEELAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMMEG 158
Cdd:cd16226  33 SKERLGIIVDKIDKNGDGFVTEEELKDWIKYVQKKYIREDVDRQWKEYDPNKDGKLSWEEYKKATYG 99

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: 36.59 E-value: 2.37e-04

                           10        20
                   ....*....|....*....|....*.
gi 4507617      55 ELDAIIEEVDEDGSGTIDFEEFLVMM 80
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLL 26

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: 39.26 E-value: 3.91e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   21 KAAFDMFDADGGGDISVKELgtvMRML--------------GQTPTKEELDAIIEEVDEDGSGTIDFEEFLV----MMVR 82
Cdd:cd15902 137 KLILKEFDANKDGKLELDEM---AKLLpvqenfllkfqilgAMDLTKEDFEKVFEHYDKDNNGVIEGNELDAllkdLLEK 213

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
gi 4507617   83 QMKEDAKGKSEEELAECFRIFDRNADGYIDPEELAEIFRAS 123
Cdd:cd15902 214 NKADIDKPDLENFRDAILRACDKNKDGKIQKTELALFLSAK 254

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: 39.19 E-value: 4.23e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617    4 QQAEARSYlsEEMIAEFKAAFDMFDADGGGDISVKELGTV--------MRMLGQTPTkeeldaiIEEVDEDGSGTIDFEE 75
Cdd:cd16230 111 DVEDAETY--KKMLARDERRFRVADQDGDSMATREELTAFlhpeefphMRDIVVAET-------LEDLDKNKDGYVQVEE 181

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 4507617   76 FLVMMVRQMKEDAKGKSEEELAECFRIF-DRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFL 153
Cdd:cd16230 182 YIADLYSGEPGEEEPAWVQTERQQFRQFrDLNKDGRLDGSEVGHWVLPPSQDQPLVEANHLLHESDTDKDGRLSKAEIL 260

EF-hand domain;

Pssm-ID: 463869 [Multi-domain] Cd Length: 30 Bit Score: 36.00 E-value: 4.53e-04

                          10        20        30
                  ....*....|....*....|....*....|
gi 4507617     95 ELAECFRIFDRNADGYIDPEELAEIFRASG 124
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

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: 38.36 E-value: 4.85e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 4507617   96 LAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLK 154
Cdd:cd16202   2 LKDQFRKADKNGDGKLSFKECKKLLKKLNVKVDKDYAKKLFQEADTSGEDVLDEEEFVQ 60

N-terminal domain of Myosin essential light chain ELC; ELC is part of the apicomplexan membrane-associated protein complex called the glideosome, which is essential for parasite motility. The glideosome is composed of six proteins: myosin A (MyoA), essential light chain ELC, myosin light chain MLC1 (also called MTIP), and the glideosome-associated proteins GAP40, GAP45, and GAP50. MyoA is a Class XIV myosin implicated in gliding motility, as well as host cell and tissue invasion by parasites. ELC binds to the MyoA neck region adjacent to the MLC1-binding site, and both myosin light chains co-located to the glideosome. Although ELCs bind to a conserved MyoA sequence, P. falciparum ELC adopts a distinct structure in the free and MyoA-bound state. Therefore ELCs enhance MyoA performance by inducing alpha helical structure formation in MyoA and thus stiffening its lever arm. It has been shown that disruption of MyoA, MLC1, or ELC have dramatic effects on parasite motility but do not affect parasite shape or replication. The ELC N-terminal domain is part of the EF-hand calcium binding motif superfamily. Calcium binding has no effect on the structure of ELCs.

Pssm-ID: 439385 [Multi-domain] Cd Length: 66 Bit Score: 36.56 E-value: 5.03e-04

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 4507617   16 MIAEFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDgsgtiDFEEFL 77
Cdd:cd22949   1 MEEKFREAFILFDRDGDGELTMYEAVLAMRSCGIPLTNDEKDALPASMNWD-----QFENWA 57

EF-hand, extracellular calcium-binding (EC) motif, found in secreted protein acidic and rich in cysteine (SPARC)-like proteins; The SPARC protein family represents a diverse group of proteins that share a follistatin-like (FS) domain and an extracellular calcium-binding (EC) domain with two EF-hand motifs. It includes SPARC (for secreted protein acidic and rich in cysteine, also termed osteonectin/ON, or basement-membrane protein 40/BM-40), SPARC-like protein 1 (for secreted protein, acidic and rich in cysteines-like 1/ SPARCL1, also termed high endothelial venule protein/Hevi, or MAST 9, or SC-1, or RAGS-1, or QR1, or ECM 2), testicans 1, 2, and 3 (also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycans, or SPOCK), secreted modular calcium-binding protein SMOC-1 (also termed SPARC-related modular calcium-binding protein 1) and SMOC-2 (also termed SPARC-related modular calcium-binding protein 2, or smooth muscle-associated protein 2/SMAP-2), follistatin-related protein 1 (FRP-1, also termed follistatin-like protein 1/fstl-1, TSC-36/Flik, TGF-beta inducible protein). The SPARC proteins have been implicated in modulating cell interaction with the extracellular milieu, including regulation of extracellular matrix assembly and deposition, counter-adhesion, effects on extracellular protease activity, and modulation of growth factor/cytokine signaling pathways, as well as in development and disease.

Pssm-ID: 320009 Cd Length: 107 Bit Score: 37.35 E-value: 6.39e-04

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 4507617  100 FRIFDRNADGYIDPEELAEIFRASG--EHVTDEEIESLmkdgDKNNDGRIDFDEFLK 154
Cdd:cd00252  51 FDNLDNNKDGKLDKRELAPFRAPLMplEHCARGFFESC----DLNKDKKISLQEWLG 103

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: 35.07 E-value: 8.25e-04

                          10        20
                  ....*....|....*....|....*.
gi 4507617     55 ELDAIIEEVDEDGSGTIDFEEFLVMM 80
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELL 26

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: 37.96 E-value: 8.34e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   59 IIEEVDEDGSGTIDFEEF--LVMMVRQMKEDakgkseeelaecFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLM 136
Cdd:cd16187  45 MISMLDRDMSGTMGFNEFkeLWAVLNGWRQH------------FISFDSDRSGTVDPQELQKALTTMGFRLSPQAVNSIA 112

                        90
                ....*....|....*..
gi 4507617  137 KDGDKNndGRIDFDEFL 153
Cdd:cd16187 113 KRYSTN--GKITFDDYI 127

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: 37.59 E-value: 8.46e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   21 KAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVRQMKEDakgkseeELAECF 100
Cdd:cd16202   3 KDQFRKADKNGDGKLSFKECKKLLKKLNVKVDKDYAKKLFQEADTSGEDVLDEEEFVQFYNRLTKRP-------EIEELF 75

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 4507617  101 RIFDRNaDGYIDPEELAEIFRASGE--HVTDEEIESLMKDGDKNNDGRID----FDEFLKMMEG 158
Cdd:cd16202  76 KKYSGD-DEALTVEELRRFLQEEQKvkDVTLEWAEQLIETYEPSEDLKAQglmsLDGFTLFLLS 138

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: 36.74 E-value: 1.02e-03

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 4507617   12 LSEEMIAEFKAAFDMFDADGGGDISVKELGTVMRML---GQTPTKEELDAIIEEVDEDGSGTIDFEEFLVM 79
Cdd:cd16251  28 LKQKSEDQIKKVFQILDKDKSGFIEEEELKYILKGFsiaGRDLTDEETKALLAAGDTDGDGKIGVEEFATL 98

S-100: S-100 domain, which represents the largest family within the superfamily of proteins carrying the Ca-binding EF-hand motif. Note that this S-100 hierarchy contains only S-100 EF-hand domains, other EF-hands have been modeled separately. S100 proteins are expressed exclusively in vertebrates, and are implicated in intracellular and extracellular regulatory activities. Intracellularly, S100 proteins act as Ca-signaling or Ca-buffering proteins. The most unusual characteristic of certain S100 proteins is their occurrence in extracellular space, where they act in a cytokine-like manner through RAGE, the receptor for advanced glycation products. Structural data suggest that many S100 members exist within cells as homo- or heterodimers and even oligomers; oligomerization contributes to their functional diversification. Upon binding calcium, most S100 proteins change conformation to a more open structure exposing a hydrophobic cleft. This hydrophobic surface represents the interaction site of S100 proteins with their target proteins. There is experimental evidence showing that many S100 proteins have multiple binding partners with diverse mode of interaction with different targets. In addition to S100 proteins (such as S100A1,-3,-4,-6,-7,-10,-11,and -13), this group includes the ''fused'' gene family, a group of calcium binding S100-related proteins. The ''fused'' gene family includes multifunctional epidermal differentiation proteins - profilaggrin, trichohyalin, repetin, hornerin, and cornulin; functionally these proteins are associated with keratin intermediate filaments and partially crosslinked to the cell envelope. These ''fused'' gene proteins contain N-terminal sequence with two Ca-binding EF-hands motif, which may be associated with calcium signaling in epidermal cells and autoprocessing in a calcium-dependent manner. In contrast to S100 proteins, "fused" gene family proteins contain an extraordinary high number of almost perfect peptide repeats with regular array of polar and charged residues similar to many known cell envelope proteins.

Pssm-ID: 238131 [Multi-domain] Cd Length: 88 Bit Score: 36.31 E-value: 1.07e-03

                        10        20        30
                ....*....|....*....|....*....|.
gi 4507617  129 DEEIESLMKDGDKNNDGRIDFDEFLKMMEGV 159
Cdd:cd00213  50 PEAVDKIMKDLDVNKDGKVDFQEFLVLIGKL 80

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: 38.05 E-value: 1.11e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   59 IIEEVDEDGSGTIDFEEFLVMMVRQMKEDAKGKSEEELAECFRIF----DRNADGYIDPEELAEIFRASGEHVTDEEIES 134
Cdd:cd16225 173 ILHDLDQDGDEKLTLDEFVSLPPGTVEEQQAEDDDEWKKERKKEFeeviDLNHDGKVTKEELEEYMDPRNERHALNEAKQ 252

                        90       100
                ....*....|....*....|...
gi 4507617  135 LMKDGDKNNDGRIDFDEFLKMME 157
Cdd:cd16225 253 LIAVADENKDGKLSLEEILKNSD 275

EF-hand domain;

Pssm-ID: 463869 [Multi-domain] Cd Length: 30 Bit Score: 34.46 E-value: 1.58e-03

                          10        20        30
                  ....*....|....*....|....*....|
gi 4507617     19 EFKAAFDMFDADGGGDISVKELGTVMRMLG 48
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

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: 34.28 E-value: 1.93e-03

                           10        20
                   ....*....|....*....|....*.
gi 4507617     131 EIESLMKDGDKNNDGRIDFDEFLKMM 156
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLL 26

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: 37.23 E-value: 2.02e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   60 IEEVDEDGSGTIDFEEFLVMMVRQMKEDAKG---KSEEELAECFRifDRNADGYIDPEELAEIFRASGEHVTDEEIESLM 136
Cdd:cd16228 161 MEDIDKNGDGFIDLEEYIGDMYSQDGDADEPewvKTEREQFTEFR--DKNKDGKMDKEETKDWILPSDYDHAEAEARHLV 238

                        90
                ....*....|....*..
gi 4507617  137 KDGDKNNDGRIDFDEFL 153
Cdd:cd16228 239 YESDQNKDGKLTKEEIV 255

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: 36.64 E-value: 2.43e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   64 DEDGSGTIDFEEFLVMMVRQMKEDAkgkseeelaeCFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGdKNN 143
Cdd:cd16188  53 DSDTTGKLGFEEFKYLWNNIKKWQG----------IYKQFDTDRSGTIGSQELPGAFEAAGFHLNEQLYQMIIRRY-SDE 121

                        90
                ....*....|
gi 4507617  144 DGRIDFDEFL 153
Cdd:cd16188 122 DGNMDFDNFI 131

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: 2.66e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   64 DEDGSGTIDFEEF--LVMMVRQMKedakgkseeelaECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESL-MKDGD 140
Cdd:cd16196  51 DVDRSGKLGFEEFkkLWEDLRSWK------------RVFKLFDTDGSGSFSSFELRNALNSAGFRLSNATLNALvLRYSN 118

                        90
                ....*....|....*.
gi 4507617  141 KnnDGRIDFDEFLKMM 156
Cdd:cd16196 119 K--DGRISFDDFIMCA 132

XopAW family type III secretion system calcium-binding effector;

Pssm-ID: 469301 [Multi-domain] Cd Length: 227 Bit Score: 36.58 E-value: 3.14e-03

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 4507617    89 KGKSEEELaecFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLKMME 157
Cdd:NF041410  25 SQQFQKQL---FAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAP 90

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: 33.51 E-value: 3.64e-03

                           10        20
                   ....*....|....*....|....*...
gi 4507617      95 ELAECFRIFDRNADGYIDPEELAEIFRA 122
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKA 28

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: 36.12 E-value: 4.78e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   66 DGSGTIDF--EEFLVMMVRQMKEDAKGKSEEELAECFRIFDRNADGYIDPEELAE-IFRASGEHVTD--EEIESLMKDGD 140
Cdd:cd16225   4 DGHLNKEFhkEVFLGNEKEEFEEDSEPKKRKKLKEIFKKVDVNTDGFLSAEELEDwIMEKTQEHFQEavEENEQIFKAVD 83

                        90
                ....*....|..
gi 4507617  141 KNNDGRIDFDEF 152
Cdd:cd16225  84 TDKDGNVSWEEY 95

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: 33.14 E-value: 5.06e-03

                          10        20
                  ....*....|....*....|....*..
gi 4507617    131 EIESLMKDGDKNNDGRIDFDEFLKMME 157
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLK 27

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: 35.84 E-value: 6.03e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   12 LSEEMIAEFKAAF-DMFDADGGGDISVKELGTVM-----------RMLGQTPTKEELDAIIEEVDEDGSGTIDFEE---F 76
Cdd:cd16178  38 ISADEVQDVKECFmSAYDVTGDGRIQIQELANIIlpddenfllffRREEPLDSSVEFMRIWRKYDADSSGYISAAElknF 117

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 4507617   77 LV-MMVRQMKEDAKGKSEEELAECFRIFDRNADGYIDPEELAEI 119
Cdd:cd16178 118 LRdLFLQHKKVITEDKLDEYTDTMMKIFDKNKDGRLDLNDMARI 161

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: 35.48 E-value: 6.18e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   17 IAEFKAAFDMFDADGGGDISVKELGTVMRMLGQTPTKEELDAIIEEVDeDGSGTIDFEEFLVMMVRQmkedakgkseEEL 96
Cdd:cd15897  69 IKAWQEIFRTYDTDGSGTIDSNELRQALSGAGYRLSEQTYDIIIRRYD-RGRGNIDFDDFIQCCVRL----------QRL 137

                        90
                ....*....|....*
gi 4507617   97 AECFRIFDRNADGYI 111
Cdd:cd15897 138 TDAFRRYDKDQDGQI 152

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: 35.76 E-value: 6.72e-03

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 4507617   92 SEEELAECFRIFDRNADGYIDPEELAEIFRASGEHVTDEEIESLMKDGDKNNDGRIDFDEFLK 154
Cdd:cd16227  34 AKRRLAVLAKKMDLNDDGFIDRKELKAWILRSFKMLDEEEANERFEEADEDGDGKVTWEEYLA 96

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: 32.35 E-value: 7.94e-03

                           10        20
                   ....*....|....*....|....*....
gi 4507617      19 EFKAAFDMFDADGGGDISVKELGTVMRML 47
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

Penta-EF hand, calcium binding motifs, found in calpain-12 (CAPN12); CAPN12, also termed calcium-activated neutral proteinase 12 (CANP 12), is a calpain large subunit mainly expressed in the cortex of the hair follicle. It may affect apoptosis regulation. CAPN12 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: 320069 [Multi-domain] Cd Length: 169 Bit Score: 35.24 E-value: 8.01e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507617   34 DISVKELGTVM-----RMLGQTPTKEELDA---IIEEVDEDGSGTIDFEEFlvmmvRQMKEDAKgkseeELAECFRIFDR 105
Cdd:cd16194  15 EINASELQKILsialeRAHTSKPREFGLRTcrqLIQCFDHGQNGKLALEEF-----QQLWGYLL-----EWQAIFTKFDE 84

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 4507617  106 NADGYIDPEELAEIFRASGEHVTDEEIESLMKDGdKNNDGRIDFDEFL 153
Cdd:cd16194  85 DTSGTMDSYELRLALNAAGFHLNNQLTETLTSRY-RDSRLRVDFESFL 131

S-100: S-100 domain, which represents the largest family within the superfamily of proteins carrying the Ca-binding EF-hand motif. Note that this S-100 hierarchy contains only S-100 EF-hand domains, other EF-hands have been modeled separately. S100 proteins are expressed exclusively in vertebrates, and are implicated in intracellular and extracellular regulatory activities. Intracellularly, S100 proteins act as Ca-signaling or Ca-buffering proteins. The most unusual characteristic of certain S100 proteins is their occurrence in extracellular space, where they act in a cytokine-like manner through RAGE, the receptor for advanced glycation products. Structural data suggest that many S100 members exist within cells as homo- or heterodimers and even oligomers; oligomerization contributes to their functional diversification. Upon binding calcium, most S100 proteins change conformation to a more open structure exposing a hydrophobic cleft. This hydrophobic surface represents the interaction site of S100 proteins with their target proteins. There is experimental evidence showing that many S100 proteins have multiple binding partners with diverse mode of interaction with different targets. In addition to S100 proteins (such as S100A1,-3,-4,-6,-7,-10,-11,and -13), this group includes the ''fused'' gene family, a group of calcium binding S100-related proteins. The ''fused'' gene family includes multifunctional epidermal differentiation proteins - profilaggrin, trichohyalin, repetin, hornerin, and cornulin; functionally these proteins are associated with keratin intermediate filaments and partially crosslinked to the cell envelope. These ''fused'' gene proteins contain N-terminal sequence with two Ca-binding EF-hands motif, which may be associated with calcium signaling in epidermal cells and autoprocessing in a calcium-dependent manner. In contrast to S100 proteins, "fused" gene family proteins contain an extraordinary high number of almost perfect peptide repeats with regular array of polar and charged residues similar to many known cell envelope proteins.

Pssm-ID: 238131 [Multi-domain] Cd Length: 88 Bit Score: 33.62 E-value: 9.26e-03

                        10        20        30        40
                ....*....|....*....|....*....|....*....|...
gi 4507617   38 KELGTVMRMLGQTPTkeeLDAIIEEVDEDGSGTIDFEEFLVMM 80
Cdd:cd00213  38 TELPNFLKNQKDPEA---VDKIMKDLDVNKDGKVDFQEFLVLI 77

Formin Homology 2 Domain; FH proteins control rearrangements of the actin cytoskeleton, especially in the context of cytokinesis and cell polarisation. Members of this family have been found to interact with Rho-GTPases, profilin and other actin-assoziated proteins. These interactions are mediated by the proline-rich FH1 domain, usually located in front of FH2 (but not listed in SMART). Despite this cytosolic function, vertebrate formins have been assigned functions within the nucleus. A set of Formin-Binding Proteins (FBPs) has been shown to bind FH1 with their WW domain.

Pssm-ID: 214697 [Multi-domain] Cd Length: 392 Bit Score: 35.40 E-value: 9.52e-03

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 4507617      33 GDISVKELGTVMRMLGQTPTKEELDAIIEEVDEDGSGTIDFEEFLVMMVR 82
Cdd:smart00498 106 GDEDVLSVDLLEQLLKYAPTKEELKKLREYKEEDPEELARAEQFLLLISN 155