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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  48 EAYSWFQSVDSDHSGYISMKELKQALVNCNWSSFNDETCLMMINMFDKTKSGRIDVYGFSALWKFIQQWKNLFQQYDRDR 127
Cdd:cd16184     1 EVQQWFQAVDRDRSGKISAKELQQALVNGNWSHFNDETCRLMIGMFDKDKSGTIDIYEFQALWNYIQQWKQVFQQFDRDR 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864 128 SGSISYTELQQALSQMGYNLSPQFTQLLVSRYCPRsANPAMQLDRFIQVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVT 207
Cdd:cd16184    81 SGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPR-ARRSLTLDQFIQVCVQLQSLTDAFRQRDTQMTGTITISYEDFLT 159

                  ....*.
gi 1034559864 208 MTASRM 213
Cdd:cd16184   160 MALLNK 165

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  48 EAYSWFQSVDSDHSGYISMKELKQALVNCNWSSFNDETCLMMINMFDKTKSGRIDVYGFSALWKFIQQWKNLFQQYDRDR 127
Cdd:cd16184     1 EVQQWFQAVDRDRSGKISAKELQQALVNGNWSHFNDETCRLMIGMFDKDKSGTIDIYEFQALWNYIQQWKQVFQQFDRDR 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864 128 SGSISYTELQQALSQMGYNLSPQFTQLLVSRYCPRsANPAMQLDRFIQVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVT 207
Cdd:cd16184    81 SGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPR-ARRSLTLDQFIQVCVQLQSLTDAFRQRDTQMTGTITISYEDFLT 159

                  ....*.
gi 1034559864 208 MTASRM 213
Cdd:cd16184   160 MALLNK 165

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  53 FQSVDSDHSGYISMKELKQALVN-CNWSSFNDETCLMMINMFDKTKSGRIDVYGFSALWK 111
Cdd:pfam13499   8 FKLLDSDGDGYLDVEELKKLLRKlEEGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

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.

                           10        20
                   ....*....|....*....|....*....
gi 1034559864  115 QWKNLFQQYDRDRSGSISYTELQQALSQM 143
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  48 EAYSWFQSVDSDHSGYISMKELKQALVNCNWSSFNDETCLMMINMFDKTKSGRIDVYGFSALWKFIQQWKNLFQQYDRDR 127
Cdd:cd16184     1 EVQQWFQAVDRDRSGKISAKELQQALVNGNWSHFNDETCRLMIGMFDKDKSGTIDIYEFQALWNYIQQWKQVFQQFDRDR 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864 128 SGSISYTELQQALSQMGYNLSPQFTQLLVSRYCPRsANPAMQLDRFIQVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVT 207
Cdd:cd16184    81 SGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPR-ARRSLTLDQFIQVCVQLQSLTDAFRQRDTQMTGTITISYEDFLT 159

                  ....*.
gi 1034559864 208 MTASRM 213
Cdd:cd16184   160 MALLNK 165

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  50 YSWFQSVDSDHSGYISMKELKQALVNCNWSSFNDETCLMMINMFDKTKSGRIDVYGFSALWKFIQQWKNLFQQYDRDRSG 129
Cdd:cd16183     3 WNVFQRVDKDRSGQISATELQQALSNGTWTPFNPETVRLMIGMFDRDNSGTINFQEFAALWKYITDWQNCFRSFDRDNSG 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864 130 SISYTELQQALSQMGYNLSPQFTQLLVSRYcPRSANPAMQLDRFIQVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVTMT 209
Cdd:cd16183    83 NIDKNELKQALTSFGYRLSDQFYDILVRKF-DRQGRGTIAFDDFIQCCVVLQTLTDSFRRYDTDQDGWIQISYEQFLEMV 161

                  ....
gi 1034559864 210 ASRM 213
Cdd:cd16183   162 FSNV 165

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+.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  48 EAYSWFQSVDSDhSGYISMKELKQALVNCNW----SSFNDETCLMMINMFDKTKSGRIDVYGFSALWKFIQQWKNLFQQY 123
Cdd:cd15897     1 QLRNVFQAVAGD-DGEISATELQQALSNVGWthfdLGFSLETCRSMIAMMDRDHSGKLNFSEFKGLWNYIKAWQEIFRTY 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864 124 DRDRSGSISYTELQQALSQMGYNLSPQFTQLLVSRYCPRSANpaMQLDRFIQVCTQLQVLTEAFREKDTAVQGNIRLSFE 203
Cdd:cd15897    80 DTDGSGTIDSNELRQALSGAGYRLSEQTYDIIIRRYDRGRGN--IDFDDFIQCCVRLQRLTDAFRRYDKDQDGQIQVNYD 157

                  ....*...
gi 1034559864 204 DFVTMTAS 211
Cdd:cd15897   158 EFLQGTMS 165

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  50 YSWFQSVdSDHSGYISMKELK----QALVNCNWSSFNDETCLMMINMFDKTKSGRIDVYGFSALWKFIQQWKNLFQQYDR 125
Cdd:cd16187     3 YGYFAAV-AGQDGQIDADELQrcltQSGIAGGYKPFNLETCRLMISMLDRDMSGTMGFNEFKELWAVLNGWRQHFISFDS 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864 126 DRSGSISYTELQQALSQMGYNLSPQFTQLLVSRYcprSANPAMQLDRFIQVCTQLQVLTEAFREKDTAVQGNIRLSFEDF 205
Cdd:cd16187    82 DRSGTVDPQELQKALTTMGFRLSPQAVNSIAKRY---STNGKITFDDYIACCVKLRALTDSFRRRDTSQQGVVNFPYDDF 158

                  ....*.
gi 1034559864 206 VTMTAS 211
Cdd:cd16187   159 IQCVMS 164

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  51 SWFQSV-DSDHSgyISMKELkQALVNCNWSS-------FNDETCLMMINMFDKTKSGRIDVYGFSALWKFIQQWKNLFQQ 122
Cdd:cd16182     4 ELFEKLaGEDEE--IDAVEL-QKLLNASLLKdmpkfdgFSLETCRSLIALMDTNGSGRLDLEEFKTLWSDLKKWQAIFKK 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864 123 YDRDRSGSISYTELQQALSQMGYNLSPQFTQLLVSRYcpRSANPAMQLDRFIQVCTQLQVLTEAFREKDTAVQGNIRLSF 202
Cdd:cd16182    81 FDTDRSGTLSSYELRKALESAGFHLSNKVLQALVLRY--ADSTGRITFEDFVSCLVRLKTAFETFSALDKKNEGVIPLTL 158

                  ....*..
gi 1034559864 203 EDFVTMT 209
Cdd:cd16182   159 EEWLLLT 165

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  64 ISMKELKQAL-------VNCNWSSFNDETCLMMINMFDKTKSGRIDVYGFSALWKFIQQWKNLFQQYDRDRSGSISYTEL 136
Cdd:cd16198    16 ISVFELKTILnriiskhKDLRTDGFSLESCRSMVNLMDKDGNGKLGLVEFNILWNKIRNYLTIFRKFDLDKSGSMSAYEM 95

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1034559864 137 QQALSQMGYNLSPQFTQLLVSRYCprSANPAMQLDRFIQVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVTMT 209
Cdd:cd16198    96 RLALESAGFKLNNRLHQVIVARYA--DPNLAIDFDNFVCCLVRLETMFRFFKQLDTEETGTIEMDLFEWLQLT 166

Penta-EF hand, calcium binding motifs, found in calpain-11 (CAPN11); CAPN11, also termed calcium-activated neutral proteinase 11 (CANP 11), is a mammalian orthologue of micro/m calpain. It is one of the calpain large subunits that appears to be exclusively expressed in certain cells of the testis. It may be involved in regulating calcium-dependent signal transduction events during meiosis and sperm functional processes. CAPN11 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  81 FNDETCLMMINMFDKTKSGRIDVYGFSALWKFIQQWKNLFQQYDRDRSGSISYTELQQALSQMGYNLSPQFTQLLVSRYC 160
Cdd:cd16193    40 FSLDVCRRMINLMDKDGSGKLGLHEFKILWKKIKKWMEIFKECDQDRSGNLNSYEMRLAIEKAGIKMNNRVTEVVVARYA 119

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 1034559864 161 prSANPAMQLDRFIQVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVTMT 209
Cdd:cd16193   120 --DDNMIVDFDSFINCFLRLKAMFAFFLSMDTKKTGSICLSINQWLQIT 166

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  81 FNDETCLMMINMFDKTKSGRIDVYGFSALWKFIQQWKNLFQQYDRDRSGSISYTELQQALSQMGYNLSPQFTQLLVSRYc 160
Cdd:cd16194    40 FGLRTCRQLIQCFDHGQNGKLALEEFQQLWGYLLEWQAIFTKFDEDTSGTMDSYELRLALNAAGFHLNNQLTETLTSRY- 118

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1034559864 161 pRSANPAMQLDRFIQvCtqLQVLTEAFREKDTAVQG 196
Cdd:cd16194   119 -RDSRLRVDFESFLS-C--LAHLTCIFCQCSQHDDG 150

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  84 ETCLMMINMFDKTKSGRIDVYGFSALWKFIQQWKNLFQQYDRDRSGSISYTELQQALSQMGYNLSPQFTQLLVSRYcprs 163
Cdd:cd16192    43 LSCKNIISLMDTSGNGKLGFSEFKVFWDKLKKWIGLFLKYDADRSGTMSSYELRSALKAAGFQLNNQLLQLIVLRY---- 118

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 1034559864 164 ANPAMQL--DRFIQVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVTMT 209
Cdd:cd16192   119 ADDYLQIdfDDFLNCLVRLENSFRVFQALDTKNTGEISLNMLEFILLT 166

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  81 FNDETCLMMINMFDKTKSGRIDVYGFSALWKFIQQWKNLFQQYDRDRSGSISYTELQQALSQMGYNLSPQFTQLLVSRYC 160
Cdd:cd16191    40 FTINTCREMISLLDTDGTGTLGLVEFRILWMKIQKYLAIYKKVDSDRSGTIDAHEMRNALQEAGFTLNNKIQQSIVQRYA 119

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 1034559864 161 prSANPAMQLDRFIQVCTQLQVLTEAFREKDTAVQGNIRLSFEDFVTMT 209
Cdd:cd16191   120 --SNKLTINFDGFIACMIRLETLFKMFQLLDKDKSGVVQLSLAEWLCCT 166

Penta-EF hand, calcium binding motifs, found in Drosophila melanogaster calpain-C (CalpC) and similar proteins; CalpC, also termed calcium-activated neutral proteinase homolog C (CANP C), is a catalytically inactive homolog of CalpA and CalpB found in Drosophila. It is strongly expressed in the salivary glands. In contrast with CalpA and CalpB, both of which 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. CalpC is a truncated calpain form missing domain I and about 20 residues from domain II. Moreover, due to all three mutated active site residues (Cys to Arg, His to Val and Asn to Ser), it may not have proteolytic activity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  79 SSFNDETCLMMINMFDKTKSGRIDVYGFSALWKFIQQWKNLFQQYDRDRSGSISYTELQQALSQMGYNLSPQFTQLLVSR 158
Cdd:cd16197    36 SCANIDVCRQVVLLMDNSGLGRLKFQDFKDFMCSLKWWQGVFKMHTKEKTGILRAERLRDALEDVGFQLNTDVLSILILR 115

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 1034559864 159 YCPRSAnpAMQLDRFIQVCTQLQVLTEAFREKDTAVQGNIRLSFEDFV 206
Cdd:cd16197   116 YMRKDG--TLRFGDFVSAVLHLTAAFGSFEKKDPLQNGFIKLSLTEWL 161

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  52 WFQSVDSDHSGYISMKELKQALVNCNWSSFNDETcLMMINMFDKTKSGRIDVYGFSALWKFIQ----QWKNLFQQYDRDR 127
Cdd:COG5126    38 LFSEADTDGDGRISREEFVAGMESLFEATVEPFA-RAAFDLLDTDGDGKISADEFRRLLTALGvseeEADELFARLDTDG 116

                          90
                  ....*....|....*...
gi 1034559864 128 SGSISYTELQQALSQMGY 145
Cdd:COG5126   117 DGKISFEEFVAAVRDYYT 134

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  52 WFQSVDSDHSGYISMKELkQALVNCNWSsfndetclMMINMFDKTKSGRIDVYGFSALWK------FIQQWKNLFQQYDR 125
Cdd:COG5126    10 RFDLLDADGDGVLERDDF-EALFRRLWA--------TLFSEADTDGDGRISREEFVAGMEslfeatVEPFARAAFDLLDT 80

                          90       100
                  ....*....|....*....|.
gi 1034559864 126 DRSGSISYTELQQALSQMGYN 146
Cdd:COG5126    81 DGDGKISADEFRRLLTALGVS 101

EF-hand domain;

                          10        20        30
                  ....*....|....*....|....*....|
gi 1034559864 115 QWKNLFQQYDRDRSGSISYTELQQALSQMG 144
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

EF-hand motif found in phosphoinositide phospholipase C delta 4 (PI-PLC-delta4); PI-PLC-delta4, also termed 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase delta-4 (PLCD4), or phospholipase C-delta-4 (PLC-delta-4), is expressed in various tissues with the highest levels detected selectively in the brain, skeletal muscle, testis and kidney. It plays a significant role in cell growth, cell proliferation, tumorigenesis, and in an early stage of fertilization. PI-PLC-delta4 may function as a key enzyme in the regulation of PtdIns(4,5)P2 levels and Ca2+ metabolism in nuclei in response to growth factors, and its expression may be partially regulated by an increase in cytoplasmic Ca2+. Moreover, PI-PLC-delta4 binds glutamate receptor-interacting protein1 (GRIP1) in testis and is required for calcium mobilization essential for the zona pellucida-induced acrosome reaction in sperm. Overexpression or dysregulated expression of PLCdelta4 may initiate oncogenesis in certain tissues through upregulating erbB1/2 expression, extracellular signal-regulated kinase (ERK) signaling pathway, and proliferation in MCF-7 cells. PI-PLC-delta4 contains an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core domain, and a 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. Unlike PI-PLC-delta 1 and 3, a putative nuclear export sequence (NES) located in the EF-hand domain, which may be responsible transporting PI-PLC-delta1 and 3 from the cell nucleus, is not present in PI-PLC-delta4.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  52 WFQSVDSDHSGYISMKELKQALVNCNwSSFNDETCLMMINMFDKTKSGRIDVYGFSALWKFIQQWKN---LFQQYDRDrS 128
Cdd:cd16219     5 WFQKADKNKDGRMNFKEVRDLLKMMN-VDMNEEHALRLFQMADKSESGTLEGEEFVLFYKALTQREDvlkIFQDFSAD-G 82

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1034559864 129 GSISYTELQQALS--QMGYNLSPQFTQLLVSRYCPRS---ANPAMQLDRFI 174
Cdd:cd16219    83 QKLTLLEFVDFLQqeQLERENTEELAMELIDRYEPSDtakKLHALSIDGFL 133

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  57 DSDHSGYISMKELKQAL-----VNCNWSSFN--DETCLMMINMFDKTKSGRIDVYGFSALW----KFIQQWKNL------ 119
Cdd:cd15902   100 DTDGSGFIEAKELKGFLkdlllKNKKHVSPPklDEYTKLILKEFDANKDGKLELDEMAKLLpvqeNFLLKFQILgamdlt 179

                          90       100
                  ....*....|....*....|....*
gi 1034559864 120 -------FQQYDRDRSGSISYTELQ 137
Cdd:cd15902   180 kedfekvFEHYDKDNNGVIEGNELD 204

EF-hand domain pair;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1034559864 113 IQQWKNLFQQYDRDRSGSISYTELQQALSQ--MGYNLSPQFTQLLV 156
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKleEGEPLSDEEVEELF 46

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864 117 KNLFQQYDRDRSGSISYTELQQALSQMGYNLSPQFTQllvsrycprsanpamqldrfiqvctqlqvltEAFREKDTavQG 196
Cdd:cd00051     3 REAFRLFDKDGDGTISADELKAALKSLGEGLSEEEID-------------------------------EMIREVDK--DG 49

                          90
                  ....*....|..
gi 1034559864 197 NIRLSFEDFVTM 208
Cdd:cd00051    50 DGKIDFEEFLEL 61

EF-hand domain;

                          10        20
                  ....*....|....*....|....*.
gi 1034559864  48 EAYSWFQSVDSDHSGYISMKELKQAL 73
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKAL 26

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.

                           10        20
                   ....*....|....*....|....*....
gi 1034559864  115 QWKNLFQQYDRDRSGSISYTELQQALSQM 143
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034559864  57 DSDHSGYISMKELKQALVN--------CNWSSFnDETCLMMINMFDKTKSGRIDVYGFSALW--------KF------IQ 114
Cdd:cd16176    95 DADHSGFIEADELKSFLKDllkkankpFDESKL-EEYTHTMLKMFDSNNDGKLGLTEMARLLpvqenfllKFqgvkmcGK 173

                          90       100
                  ....*....|....*....|....*....
gi 1034559864 115 QWKNLFQQYDRDRSGSISYTELQQALSQM 143
Cdd:cd16176   174 EFNKIFELYDQDGNGYIDENELDALLKDL 202