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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1370463245 242 ELRDAFREFDTNGDGEISTSELREAMRKLlGHQVGHRDIEEIIRDVDLNGDGRVDFEEFVRMMS 305
Cdd:cd00051     1 ELREAFRLFDKDGDGTISADELKAALKSL-GEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1370463245 241 KELRDAFREFDTNGDGEISTSELREAMRKLLGHQVGHRD-IEEIIRDVDLNGDGRVDFEEFVRMMS 305
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEPLSDEeVEELFKEFDLDKDGRISFEEFLELYS 67

XopAW family type III secretion system calcium-binding effector;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1370463245 241 KELrdaFREFDTNGDGEISTSELREAMR-----KLLGhqvghrDIEEIIRDVDLNGDGRVDFEEFVRMM 304
Cdd:NF041410   30 KQL---FAKLDSDGDGSVSQDELSSALSsksddGSLI------DLSELFSDLDSDGDGSLSSDELAAAA 89

centrin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463245 157 SLRPEEIEELREAFREFDKDKDGYINCRDLGNCMRTMGYMPTEMELIELSQQINMNLGGHVDFDDFVELMGPKLlaetAD 236
Cdd:PTZ00183   10 GLTEDQKKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMTKKL----GE 85

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463245 237 MIGVKELRDAFREFDTNGDGEISTSELREAMRKlLGHQVGHRDIEEIIRDVDLNGDGRVDFEEFVRMMSR 306
Cdd:PTZ00183   86 RDPREEILKAFRLFDDDKTGKISLKNLKRVAKE-LGETITDEELQEMIDEADRNGDGEISEEEFYRIMKK 154

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463245 161 EEIEELREAFREFDKDKDGYINCRDLGNCMRTMgymptemeLIELSQQINMNLGGHVDFDDFVELMGPKLLAETADmigv 240
Cdd:COG5126     2 LQRRKLDRRFDLLDADGDGVLERDDFEALFRRL--------WATLFSEADTDGDGRISREEFVAGMESLFEATVEP---- 69

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1370463245 241 kELRDAFREFDTNGDGEISTSELREAMRkllGHQVGHRDIEEIIRDVDLNGDGRVDFEEFVRMM 304
Cdd:COG5126    70 -FARAAFDLLDTDGDGKISADEFRRLLT---ALGVSEEEADELFARLDTDGDGKISFEEFVAAV 129

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+.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463245 165 ELREAFREFDKDKDGYINCRDLGNCMRTMGYMPTEMELIELsqQINM---NLGGHVDFDDFVELMgpkllaetadmigvK 241
Cdd:cd16180     1 ELRRIFQAVDRDRSGRISAKELQRALSNGDWTPFSIETVRL--MINMfdrDRSGTINFDEFVGLW--------------K 64

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1370463245 242 ELRD---AFREFDTNGDGEISTSELREAMRKlLGHQVGHRDIEEIIRDVDLNGDGRVDFEEFVRMM 304
Cdd:cd16180    65 YIQDwrrLFRRFDRDRSGSIDFNELQNALSS-FGYRLSPQFVQLLVRKFDRRRRGSISFDDFVEAC 129

calmodulin; Provisional

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1370463245 240 VKELRDAFREFDTNGDGEISTSELREAMRKLlGHQVGHRDIEEIIRDVDLNGDGRVDFEEFVRMMSR 306
Cdd:PTZ00184   10 IAEFKEAFSLFDKDGDGTITTKELGTVMRSL-GQNPTEAELQDMINEVDADGNGTIDFPEFLTLMAR 75

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463245 158 LRPEEIEE-LREAFREFDKDKDGYIncrdlgncmrtmgympTEMEL---IELSQQ-------------INMNLGGHVDFD 220
Cdd:cd16226    28 LTPEESKErLGIIVDKIDKNGDGFV----------------TEEELkdwIKYVQKkyiredvdrqwkeYDPNKDGKLSWE 91

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463245 221 DFVELMGPKLLAETADMIGVKELRDA-------FREFDTNGDGEISTSELR--------EAMRKLLghqvghrdIEEIIR 285
Cdd:cd16226    92 EYKKATYGFLDDEEEDDDLHESYKKMirrderrWKAADQDGDGKLTKEEFTaflhpeefPHMRDIV--------VQETLE 163

                         170
                  ....*....|....*.
gi 1370463245 286 DVDLNGDGRVDFEEFV 301
Cdd:cd16226   164 DIDKNKDGFISLEEYI 179

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 1370463245 168 EAFREFDKDKDGYINCRDLGNCMRTM-----GYMPTEMELIELSQQI----NMNLGGHVDFDDFVELMGP-----KLLAE 233
Cdd:cd15902     3 EVWMHFDADGNGYIEGKELDSFLRELlkalnGKDKTDDEVAEKKKEFmekyDENEDGKIEIRELANILPTeenflLLFRR 82

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1370463245 234 TADMIGVKELRDAFREFDTNGDGEISTSELREAMRKLLGHQVGHRD-------IEEIIRDVDLNGDGRVDFEEFVRMM 304
Cdd:cd15902    83 EQPLISSVEFMKIWRKYDTDGSGFIEAKELKGFLKDLLLKNKKHVSppkldeyTKLILKEFDANKDGKLELDEMAKLL 160

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463245 215 GHVDFDDFVELMGPkllaetadmigvkELRDAFREFDTNGDGEISTSELREAMRKLLGhQVGHRDIEEIIRDVDLNGDGR 294
Cdd:COG5126    20 GVLERDDFEALFRR-------------LWATLFSEADTDGDGRISREEFVAGMESLFE-ATVEPFARAAFDLLDTDGDGK 85

                          90
                  ....*....|.
gi 1370463245 295 VDFEEFVRMMS 305
Cdd:COG5126    86 ISADEFRRLLT 96

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1370463245 163 IEELREAFREFDKDKDGYINCRDLGNCMRTMGYM--PTEMELIELSQQINMNLGGHVDFDDFVELM 226
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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463245 163 IEELREAFREFDKDKDGYINCRDLGNCMRTMGYmptemeliELSQQI--------NMNLGGHVDFDDFVELmgpkllaet 234
Cdd:cd16183    66 ITDWQNCFRSFDRDNSGNIDKNELKQALTSFGY--------RLSDQFydilvrkfDRQGRGTIAFDDFIQC--------- 128

                          90       100
                  ....*....|....*....|....*..
gi 1370463245 235 adMIGVKELRDAFREFDTNGDGEISTS 261
Cdd:cd16183   129 --CVVLQTLTDSFRRYDTDQDGWIQIS 153

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 1370463245 165 ELREAFREFDKDkDGYINCRDLGNCMRTMGYMPTEME--LIELSQQINM---NLGGHVDFDDFVELMGpkllaetadmiG 239
Cdd:cd15897     1 QLRNVFQAVAGD-DGEISATELQQALSNVGWTHFDLGfsLETCRSMIAMmdrDHSGKLNFSEFKGLWN-----------Y 68

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1370463245 240 VKELRDAFREFDTNGDGEISTSELREAMrKLLGHQVGHRDIEEIIRDVDlNGDGRVDFEEFV 301
Cdd:cd15897    69 IKAWQEIFRTYDTDGSGTIDSNELRQAL-SGAGYRLSEQTYDIIIRRYD-RGRGNIDFDDFI 128

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 1370463245 163 IEELREAFREFDKDKDGYINCRDLGNCMRTMGYMPTEmeliELSQQINMNLG---GHVDFDDFVELmgpkllaetadMIG 239
Cdd:cd15897    69 IKAWQEIFRTYDTDGSGTIDSNELRQALSGAGYRLSE----QTYDIIIRRYDrgrGNIDFDDFIQC-----------CVR 133

                          90
                  ....*....|....*....
gi 1370463245 240 VKELRDAFREFDTNGDGEI 258
Cdd:cd15897   134 LQRLTDAFRRYDKDQDGQI 152

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).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463245 165 ELREAFREFDKDKDGYINCRDLGNcMRTMGYMPTEMELIElsQQINM---NLGGHVDFDDFVELMgpKLLAEtadmigvk 241
Cdd:cd16185     1 ELRQWFRAVDRDRSGSIDVNELQK-ALAGGGLLFSLATAE--KLIRMfdrDGNGTIDFEEFAALH--QFLSN-------- 67

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1370463245 242 eLRDAFREFDTNGDGEISTSELREAMRKlLGHQVGHRDIEEIIRDVDLNGDGRVDFEEFVRM 303
Cdd:cd16185    68 -MQNGFEQRDTSRSGRLDANEVHEALAA-SGFQLDPPAFQALFRKFDPDRGGSLGFDDYIEL 127

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1370463245 243 LRDAFREFDTNGDGEISTSELREAMrkllghqvgHRDIEEIIRDVDLNGDGRVDFEEFVRMMSR 306
Cdd:COG5126     7 LDRRFDLLDADGDGVLERDDFEALF---------RRLWATLFSEADTDGDGRISREEFVAGMES 61

EF-hand, calcium binding motif, found in calretinin (CR); CR, also termed 29 kDa calbindin, 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 possibly functions as a calcium buffer, calcium sensor, and apoptosis regulator, which may be implicated in many biological processes, including cell proliferation, differentiation, and cell death. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. CR I-II consists of EF-hand motifs 1 and 2, and CR III-VI consists of EF-hand motifs 3-6. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. Thus, CR has two pairs of cooperative binding sites (I-II and III-IV), which display high affinity calcium-binding sites, and one independent calcium ion-binding site (V), which displays lower affinity binding.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463245 168 EAFREFDKDKDGYINCRDLGNCMRTM-------GYMPT----EMELIELSQQINMNLGGHVDFDDFVELMGPK---LLAE 233
Cdd:cd16177     3 EIWKHFDADGNGYIEGKELENFFRELerarrgaGVDSKsanfGEKMKEFMQKYDKNADGRIEMAELAQILPTEenfLLCF 82

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1370463245 234 TADMIGVKELRDAFREFDTNGDGEISTSELREAMRKLLGHQVGHRD-------IEEIIRDVDLNGDGRVDFEEFVRMM 304
Cdd:cd16177    83 RQHVGSSSEFMEAWRKYDTDRSGYIEANELKGFLSDLLKKANRPYDekklqeyTQTILRMFDLNGDGKLGLSEMARLL 160

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 1370463245 163 IEELREAFREFDKDKDGYINCRDLGNCMRTMGYMPTEMELIELSQQINMNLGGHVDFDDFVELmgpkllaetadMIGVKE 242
Cdd:cd16184    66 IQQWKQVFQQFDRDRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRARRSLTLDQFIQV-----------CVQLQS 134

                          90
                  ....*....|....*....
gi 1370463245 243 LRDAFREFDTNGDGEISTS 261
Cdd:cd16184   135 LTDAFRQRDTQMTGTITIS 153

EF-hand domain;

                          10        20        30
                  ....*....|....*....|....*....|
gi 1370463245 165 ELREAFREFDKDKDGYINCRDLGNCMRTMG 194
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463245 146 KGFAENRQPDRSLRPEEIEELREAFRE-FDKDKDGYINCRDLGNcmrtmgYMPTEMELIELSQQINMNLgghvdfDDFVE 224
Cdd:cd16178    26 KDLLKKLGTKDTISADEVQDVKECFMSaYDVTGDGRIQIQELAN------IILPDDENFLLFFRREEPL------DSSVE 93

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463245 225 LMgpkllaetadmigvkelrDAFREFDTNGDGEISTSELREAMRKLLgHQVGHRDIEE--------IIRDVDLNGDGRVD 296
Cdd:cd16178    94 FM------------------RIWRKYDADSSGYISAAELKNFLRDLF-LQHKKVITEDkldeytdtMMKIFDKNKDGRLD 154

                  ....*....
gi 1370463245 297 FEEFVRMMS 305
Cdd:cd16178   155 LNDMARILA 163

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 1370463245 164 EELREAFREFDKDKDGYINCRDLGNCMRTM----GYMPTEMELIELSQQI----NMNLGGHVDFDDFVELMGPKL-LAET 234
Cdd:cd15902    90 VEFMKIWRKYDTDGSGFIEAKELKGFLKDLllknKKHVSPPKLDEYTKLIlkefDANKDGKLELDEMAKLLPVQEnFLLK 169

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1370463245 235 ADMIGVKELR-----DAFREFDTNGDGEISTSELREAMRKLLGHQVGHRDIEE-------IIRDVDLNGDGRVDFEEFV 301
Cdd:cd15902   170 FQILGAMDLTkedfeKVFEHYDKDNNGVIEGNELDALLKDLLEKNKADIDKPDlenfrdaILRACDKNKDGKIQKTELA 248

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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1370463245 254 GDGE-ISTSELREAMRK----LLGHQVGHRDIEEIIRDVDLNGDGRVDFEEFVRMM 304
Cdd:cd00213    22 GDKDtLSKKELKELLETelpnFLKNQKDPEAVDKIMKDLDVNKDGKVDFQEFLVLI 77

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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463245 233 ETADMIGVKELRDAFREFDTNGDGEISTSELRE-AMRKLLGH-QVGHRDIEEIIRDVDLNGDGRVDFEEF 300
Cdd:cd16225    26 EDSEPKKRKKLKEIFKKVDVNTDGFLSAEELEDwIMEKTQEHfQEAVEENEQIFKAVDTDKDGNVSWEEY 95

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463245 162 EIEELREAFREFDKDKDGYINCRDLGNCMrtmgymptemelielsqqinmnLGGHVDFDDFVElmgpkllAETADMIGVK 241
Cdd:cd15899    69 AMEESKEQFRAVDPDEDGHVSWDEYKNDT----------------------YGSVGDDEENVA-------DNIKEDEEYK 119

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1370463245 242 EL----RDAFREFDTNGDGEISTSEL------REA--MRKLLghqvghrdIEEIIRDVDLNGDGRVDFEEFV 301
Cdd:cd15899   120 KLllkdKKRFEAADQDGDLILTLEEFlaflhpEESpyMLDFV--------IKETLEDLDKNGDGFISLEEFI 183

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1370463245 245 DAFREFDTNGDGEISTSELREAMRK------LLGHqvghrdieeIIRDVDLNGDGRVDFEEFV 301
Cdd:cd00052     3 QIFRSLDPDGDGLISGDEARPFLGKsglprsVLAQ---------IWDLADTDKDGKLDKEEFA 56

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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1370463245 247 FREFDTNGDGEISTSELREAMRKLlGHQVGHRDIEEIIRDVDLNGDGRVDFEEFVRMM 304
Cdd:cd16226    41 VDKIDKNGDGFVTEEELKDWIKYV-QKKYIREDVDRQWKEYDPNKDGKLSWEEYKKAT 97

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).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463245 156 RSLRPEEIEELREAFREFDKDKDGYINCRDLGNCM--RTMGY---MPTEMELIELSQQI-----------NMNLGGHVDF 219
Cdd:cd16224    64 QSFRHYALEDAKQQFPEYDKDGDGAVTWDEYNMQMydRVIDYdedTVLDDEEEESFRQLhlkdkkrfdkaNTDGGPGLNL 143

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1370463245 220 DDFVELMGPkllaETADMIGVKELRDAFREFDTNGDGEISTSELREAMRKLLG-HQVGHRDIEEIIR---DVDLNGDGRV 295
Cdd:cd16224   144 TEFIAFEHP----EEVDYMTEFVIQEALEEHDKDGDGFISLEEFLGDYRKDPTaNEDPEWIIVEKDRfvnDYDKDNDGKL 219

                  ....*..
gi 1370463245 296 DFEEFVR 302
Cdd:cd16224   220 DPQELLP 226

phosphatidylserine decarboxylase

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1370463245 251 DTNGDGEISTSELREAMrKLLGHQVGHRDIEEIIRDVDLNGDGRVDFEEFVRMMS 305
Cdd:PLN02964  189 DYDEDGQLSFSEFSDLI-KAFGNLVAANKKEELFKAADLNGDGVVTIDELAALLA 242

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.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1370463245 244 RDAFREFDTNGDGEISTSELREAMrkllgHQVGHRDIEEIIRDVDL---NGDGRVDFEEFVRMMSR 306
Cdd:cd16196    74 KRVFKLFDTDGSGSFSSFELRNAL-----NSAGFRLSNATLNALVLrysNKDGRISFDDFIMCAVK 134

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.

                          10        20
                  ....*....|....*....|....*.
gi 1370463245 243 LRDAFREFDTNGDGEISTSELREAMR 268
Cdd:cd22949     5 FREAFILFDRDGDGELTMYEAVLAMR 30

S-100A10_like: S-100A10 domain found in proteins similar to S100A10. S100A10 is a member of the S100 family of EF-hand superfamily of calcium-binding proteins. Note that the S-100 hierarchy, to which this S-100A1_like group belongs, 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. A unique feature of S100A10 is that it contains mutation in both of the calcium binding sites, making it calcium insensitive. S100A10 has been detected in brain, heart, gastrointestinal tract, kidney, liver, lung, spleen, testes, epidermis, aorta, and thymus. Structural data supports the homo- and hetero-dimeric as well as hetero-tetrameric nature of the protein. S100A10 has multiple binding partners in its calcium free state and is therefore involved in many diverse biological functions.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1370463245 256 GEISTSELREAMRK----LLGHQVGHRDIEEIIRDVDLNGDGRVDFEEFV 301
Cdd:cd05031    25 NTLSRKELKKLMEKelseFLKNQKDPMAVDKIMKDLDQNRDGKVNFEEFV 74

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 1370463245 170 FREFDKDKDGYINCRDLGNCMRTMGYMPTEMELIELsqQINM---NLGGHVDFDDFVELMgpKLlaetadmigVKELRDA 246
Cdd:cd16183     6 FQRVDKDRSGQISATELQQALSNGTWTPFNPETVRL--MIGMfdrDNSGTINFQEFAALW--KY---------ITDWQNC 72

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1370463245 247 FREFDTNGDGEISTSELREAMRKlLGHQVGHRDIEEIIRDVDLNGDGRVDFEEFV 301
Cdd:cd16183    73 FRSFDRDNSGNIDKNELKQALTS-FGYRLSDQFYDILVRKFDRQGRGTIAFDDFI 126