WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from its N-terminus and the WD dipeptide at its C-terminus and is 40 residues long, hence the name WD40; between GH and WD lies a conserved core; serves as a stable propeller-like platform to which proteins can bind either stably or reversibly; forms a propeller-like structure with several blades where each blade is composed of a four-stranded anti-parallel b-sheet; instances with few detectable copies are hypothesized to form larger structures by dimerization; each WD40 sequence repeat forms the first three strands of one blade and the last strand in the next blade; the last C-terminal WD40 repeat completes the blade structure of the first WD40 repeat to create the closed ring propeller-structure; residues on the top and bottom surface of the propeller are proposed to coordinate interactions with other proteins and/or small ligands; 7 copies of the repeat are present in this alignment.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1820676344  16 GHELDVRGLShgLFPPGG-FVSVSRDRTARLWAPdgpnRGFTEMHCMRGHSNFVSCVCIIPSSDiyprgLIATGGNDHNI 94
Cdd:cd00200   175 GHTGEVNSVA--FSPDGEkLLSSSSDGTIKLWDL----STGKCLGTLRGHENGVNSVAFSPDGY-----LLASGSEDGTI 243

                          90
                  ....*....|....*....
gi 1820676344  95 CIFTLDSTAPLYVLKGHKN 113
Cdd:cd00200   244 RVWDLRTGECVQTLSGHTN 262

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1820676344 176 EDIKKIFHILDKDRSGFIEENELKFILKGFtSNGRDLSDKETKTLLAAGDKDGDGKIGIDEFITLV 241
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKL-EEGEPLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1820676344 176 EDIKKIFHILDKDRSGFIEENELKFILKGFtsngrDLSDKETKTLLAAGDKDGDGKIGIDEFITLVAE 243
Cdd:COG5126    69 PFARAAFDLLDTDGDGKISADEFRRLLTAL-----GVSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

WD40 repeat [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1820676344   7 TYRLRCSVVGHELDVRGLShglFPPGG--FVSVSRDRTARLWAPDGPNRGFTemhcMRGHSNFVSCVCIIPSSDiyprgL 84
Cdd:COG2319   235 TGKLLRTLTGHSGSVRSVA---FSPDGrlLASGSADGTVRLWDLATGELLRT----LTGHSGGVNSVAFSPDGK-----L 302

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1820676344  85 IATGGNDHNICIFTLDSTAPLYVLKGHKNTGR 116
Cdd:COG2319   303 LASGSDDGTVRLWDLATGKLLRTLTGHTGAVR 334

WD40 repeats; Note that these repeats are permuted with respect to the structural repeats (blades) of the beta propeller domain.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|...
gi 1820676344   55 FTEMHCMRGHSNFVSCVCIIPSSDiyprgLIATGGNDHNICIF 97
Cdd:smart00320   2 GELLKTLKGHTGPVTSVAFSPDGK-----YLASGSDDGTIKLW 39

WD domain, G-beta repeat;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1820676344  55 FTEMHCMRGHSNFVSCVCIIPSSDiyprgLIATGGNDHNICIF 97
Cdd:pfam00400   1 GKLLKTLEGHTGSVTSLAFSPDGK-----LLASGSDDGTVKVW 38

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1820676344 151 SSLAAAESFCHKKFFEMVGLKKKSQEDIKKIFHILDKDRSGFIEENELKFILKGFTSNGRDLSDKETKTLLAAGDKDGDG 230
Cdd:cd16251     9 SAFRAHGSFNYKKFFEHVGLKQKSEDQIKKVFQILDKDKSGFIEEEELKYILKGFSIAGRDLTDEETKALLAAGDTDGDG 88

                          90
                  ....*....|...
gi 1820676344 231 KIGIDEFITLVAE 243
Cdd:cd16251    89 KIGVEEFATLVAG 101

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).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1820676344 151 SSLAAAESFCHKKFFEMVGLKKKSQEDIKKIFHILDKDRSGFIEENELKFILKGFTSNGRDLSDKETKTLLAAGDKDGDG 230
Cdd:cd16255     9 SQCQAADSFNFKKFFATSGLSKKSADDVKKVFEIIDQDKSGFIEEEELKLFLQNFSSGARELTDAETKAFLKAGDSDGDG 88

                          90
                  ....*....|.
gi 1820676344 231 KIGIDEFITLV 241
Cdd:cd16255    89 KIGVEEFQALV 99

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 1820676344 177 DIKKIFHILDKDRSGFIEENELKFILKGFtsnGRDLSDKETKTLLAAGDKDGDGKIGIDEFITLVA 242
Cdd:cd00051     1 ELREAFRLFDKDGDGTISADELKAALKSL---GEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1820676344 171 KKKSQEDIKKIFHILDKDRSGFIEENELKFILKG-FTSNGRDLS----DKETKTLLAAGDKDGDGKIGIDEFITL 240
Cdd:cd15902    85 PLISSVEFMKIWRKYDTDGSGFIEAKELKGFLKDlLLKNKKHVSppklDEYTKLILKEFDANKDGKLELDEMAKL 159

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1820676344 176 EDIKKIFHILDKDRSGFIEENELKFILKGFtsngrDLSDKETKTLLAAGDKDGDGKIGIDEFITLVAE 243
Cdd:COG5126    69 PFARAAFDLLDTDGDGKISADEFRRLLTAL-----GVSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

WD40 repeat [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1820676344   7 TYRLRCSVVGHELDVRGLShglFPPGG--FVSVSRDRTARLWAPDGPNRGFTemhcMRGHSNFVSCVCIIPSSDiyprgL 84
Cdd:COG2319   235 TGKLLRTLTGHSGSVRSVA---FSPDGrlLASGSADGTVRLWDLATGELLRT----LTGHSGGVNSVAFSPDGK-----L 302

                          90       100       110
                  ....*....|....*....|....*....|..
gi 1820676344  85 IATGGNDHNICIFTLDSTAPLYVLKGHKNTGR 116
Cdd:COG2319   303 LASGSDDGTVRLWDLATGKLLRTLTGHTGAVR 334

WD40 repeat [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1820676344   2 ASAGGTYRL--------RCSVVGHELDVRGLShglFPPGG--FVSVSRDRTARLWAPDGPNRGFTemhcMRGHSNFVSCV 71
Cdd:COG2319    96 ASADGTVRLwdlatgllLRTLTGHTGAVRSVA---FSPDGktLASGSADGTVRLWDLATGKLLRT----LTGHSGAVTSV 168

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1820676344  72 CIIPSSDiyprgLIATGGNDHNICIFTLDSTAPLYVLKGHKN 113
Cdd:COG2319   169 AFSPDGK-----LLASGSDDGTVRLWDLATGKLLRTLTGHTG 205

WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from its N-terminus and the WD dipeptide at its C-terminus and is 40 residues long, hence the name WD40; between GH and WD lies a conserved core; serves as a stable propeller-like platform to which proteins can bind either stably or reversibly; forms a propeller-like structure with several blades where each blade is composed of a four-stranded anti-parallel b-sheet; instances with few detectable copies are hypothesized to form larger structures by dimerization; each WD40 sequence repeat forms the first three strands of one blade and the last strand in the next blade; the last C-terminal WD40 repeat completes the blade structure of the first WD40 repeat to create the closed ring propeller-structure; residues on the top and bottom surface of the propeller are proposed to coordinate interactions with other proteins and/or small ligands; 7 copies of the repeat are present in this alignment.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1820676344   7 TYRLRCSVVGHELDVRGLShglFPPGG--FVSVSRDRTARLWapDGPNRGFTemHCMRGHSNFVSCVCIIPSSDiyprgL 84
Cdd:cd00200    82 TGECVRTLTGHTSYVSSVA---FSPDGriLSSSSRDKTIKVW--DVETGKCL--TTLRGHTDWVNSVAFSPDGT-----F 149

                          90       100
                  ....*....|....*....|....*....
gi 1820676344  85 IATGGNDHNICIFTLDSTAPLYVLKGHKN 113
Cdd:cd00200   150 VASSSQDGTIKLWDLRTGKCVATLTGHTG 178

centrin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1820676344 162 KKFFEMVGLKKKSQEDIKKIFHILDKDRSGFIEENELKFILKgftSNGRDLSDKETKTLLAAGDKDGDGKIGIDEFITLV 241
Cdd:PTZ00183    3 KRRSERPGLTEDQKKEIREAFDLFDTDGSGTIDPKELKVAMR---SLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIM 79

                  .
gi 1820676344 242 A 242
Cdd:PTZ00183   80 T 80

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1820676344 165 FEMVGLKKKSQEDIKKIFHILDKDRSGFIEENELKFILKG-FTSNGRDLS----DKETKTLLAAGDKDGDGKIGIDE 236
Cdd:cd15902   170 FQILGAMDLTKEDFEKVFEHYDKDNNGVIEGNELDALLKDlLEKNKADIDkpdlENFRDAILRACDKNKDGKIQKTE 246

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1820676344 164 FFEMVGLKKKSQeDIKKIFHILDKDRSGFIEENELKfilKGFTSNGRDLSDKETKTLLAAGDKDGDGKIGIDEFI 238
Cdd:cd16183    56 FQEFAALWKYIT-DWQNCFRSFDRDNSGNIDKNELK---QALTSFGYRLSDQFYDILVRKFDRQGRGTIAFDDFI 126

WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from its N-terminus and the WD dipeptide at its C-terminus and is 40 residues long, hence the name WD40; between GH and WD lies a conserved core; serves as a stable propeller-like platform to which proteins can bind either stably or reversibly; forms a propeller-like structure with several blades where each blade is composed of a four-stranded anti-parallel b-sheet; instances with few detectable copies are hypothesized to form larger structures by dimerization; each WD40 sequence repeat forms the first three strands of one blade and the last strand in the next blade; the last C-terminal WD40 repeat completes the blade structure of the first WD40 repeat to create the closed ring propeller-structure; residues on the top and bottom surface of the propeller are proposed to coordinate interactions with other proteins and/or small ligands; 7 copies of the repeat are present in this alignment.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1820676344  10 LRCSVVGHELDVRGLShgLFPPGGF-VSVSRDRTARLWAPDGPnrgfTEMHCMRGHSNFVSCVCIIPSSDiyprgLIATG 88
Cdd:cd00200     1 LRRTLKGHTGGVTCVA--FSPDGKLlATGSGDGTIKVWDLETG----ELLRTLKGHTGPVRDVAASADGT-----YLASG 69

                          90       100
                  ....*....|....*....|....*
gi 1820676344  89 GNDHNICIFTLDSTAPLYVLKGHKN 113
Cdd:cd00200    70 SSDKTIRLWDLETGECVRTLTGHTS 94

WD40 repeat [General function prediction only];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1820676344   6 GTYRLRCSVVGHELDVRGLShglFPPGG--FVSVSRDRTARLWAPDGPnrgfTEMHCMRGHSNFVSCVCIIPSSDiyprg 83
Cdd:COG2319   318 ATGKLLRTLTGHTGAVRSVA---FSPDGktLASGSDDGTVRLWDLATG----ELLRTLTGHTGAVTSVAFSPDGR----- 385

                          90
                  ....*....|....*...
gi 1820676344  84 LIATGGNDHNICIFTLDS 101
Cdd:COG2319   386 TLASGSADGTVRLWDLAT 403

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1820676344 177 DIKKIFHILDKDRSGFIEENELKFILKgfTSNGRDLSDKETKTLLAAGDKDGDGKIGIDEFITL 240
Cdd:cd16180     1 ELRRIFQAVDRDRSGRISAKELQRALS--NGDWTPFSIETVRLMINMFDRDRSGTINFDEFVGL 62

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.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1820676344 174 SQEDIKKIFHILDKDRSGFIEENELKFILKGFTSNGRDLSDKE-------TKTLLAAGDKDGDGKIGIDEFITLV 241
Cdd:cd16179    93 SSVEFMKVWREYDKDNSGYIEADELKNFLKHLLKEAKRDNDVSedklieyTDTILQLFDRNKDGKLQLSEMARLL 167

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1820676344 177 DIKKIFHILDKDRSGFIEENELK-FILKGFTSNGRDLSDKE----TKTLLAAGDKDGDGKIGIDEFITLVA 242
Cdd:cd16178    93 EFMRIWRKYDADSSGYISAAELKnFLRDLFLQHKKVITEDKldeyTDTMMKIFDKNKDGRLDLNDMARILA 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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1820676344 180 KIFHILDKDRSGFIEENELKFILKGF--TSNGRDLSD----KETKTLLAAGDKDGDGKIGIDEF 237
Cdd:cd15902     3 EVWMHFDADGNGYIEGKELDSFLRELlkALNGKDKTDdevaEKKKEFMEKYDENEDGKIEIREL 66

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1820676344 147 QPHSSSLAAAESFCHK---KFFEMVGLKKkSQEDIKKIFHILDKDRSGFIEENELK-FILKGFTSNGRDlsdkETKTLLA 222
Cdd:cd15899     4 DGHLNSDYDHEAFLGKeeaEEFDQLTPEE-SKRRLGVIVSKMDVDKDGFISAKELHsWILESFKRHAME----ESKEQFR 78

                          90
                  ....*....|....*.
gi 1820676344 223 AGDKDGDGKIGIDEFI 238
Cdd:cd15899    79 AVDPDEDGHVSWDEYK 94

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).

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                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1820676344 182 FHILDKDRSGFIEENELKFILkgfTSNGRDLSDKETKTLLAAGDKDGDGKIGIDEFITL 240
Cdd:cd16185     6 FRAVDRDRSGSIDVNELQKAL---AGGGLLFSLATAEKLIRMFDRDGNGTIDFEEFAAL 61

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.

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                  ....*....|....*....|....*..
gi 1820676344 177 DIKKIFHILDKDRSGFIEENELKFILK 203
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLK 27

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.

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                   ....*....|....*....|....*..
gi 1820676344  177 DIKKIFHILDKDRSGFIEENELKFILK 203
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLK 27

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1820676344 177 DIKKIFHILDKDRSGFIEENELKFILKGFtsNGRDLSDKETKTLLAAGDKDGDGKIGIDEF 237
Cdd:cd16184     1 EVQQWFQAVDRDRSGKISAKELQQALVNG--NWSHFNDETCRLMIGMFDKDKSGTIDIYEF 59

calmodulin; Provisional

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1820676344 174 SQEDI---KKIFHILDKDRSGFIEENELKFILKgftSNGRDLSDKETKTLLAAGDKDGDGKIGIDEFITLVA 242
Cdd:PTZ00184    6 TEEQIaefKEAFSLFDKDGDGTITTKELGTVMR---SLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMA 74

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).

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1820676344 174 SQEDIKKIFHILDKDRSGFIEENELK-FILKGFTSngrdLSDKETKTLLAAGDKDGDGKIGIDEFIT 239
Cdd:cd16227    34 AKRRLAVLAKKMDLNDDGFIDRKELKaWILRSFKM----LDEEEANERFEEADEDGDGKVTWEEYLA 96

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1820676344 180 KIFHILDKDRSGFIEENELK-FI---LKGFTSNGRDLSDkETKTLLAAGDKDGDGKIGIDEF 237
Cdd:cd16176     3 EIWHHYDNDGNGYIEGKELQsFIqelQQARKKAGLELSD-QMKAFVDQYGQSTDGKIGIVEL 63

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1820676344 179 KKIFHILDKDRSGFIEENELKFILKGFtsnGRDLSDKETKTLLAAGDKdgDGKIGIDEFITL 240
Cdd:cd16181    73 KTTFMQYDRDRSGTVEPQELQQAIRSF---GYNLSPQALNVIVKRYSK--NGRITFDDFVAC 129

XopAW family type III secretion system calcium-binding effector;

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1820676344 171 KKKSQEDIKKIFHILDKDRSGFIEENELKFILK------GFTSNGRDLSDketktLLAAGDKDGDGKIGIDEFITLVAEA 244
Cdd:NF041410   58 DDGSLIDLSELFSDLDSDGDGSLSSDELAAAAPppppppDQAPSTELADD-----LLSALDTDGDGSISSDELSAGLTSA 132

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.

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                  ....*....|....*....|....*....|....*....|....*....
gi 1820676344 172 KKSQEDIKKIFHILDKDRSGFIEENELKFILKgftsngrDLSDKETKTL 220
Cdd:cd16177   174 KLSSEEFNAIFAFYDKDGSGYIDENELDALLK-------DLYEKNKKEM 215

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1820676344 174 SQEDIKKIFHILDKDRSGFIEENELK-FILKGFTSNGRDLSDKETKTLlaagDKDGDGKIGIDEF 237
Cdd:cd16226    33 SKERLGIIVDKIDKNGDGFVTEEELKdWIKYVQKKYIREDVDRQWKEY----DPNKDGKLSWEEY 93

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+.

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                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1820676344 181 IFHILDKDrSGFIEENELKFILKGFTSNGRDL--SDKETKTLLAAGDKDGDGKIGIDEF 237
Cdd:cd15897     5 VFQAVAGD-DGEISATELQQALSNVGWTHFDLgfSLETCRSMIAMMDRDHSGKLNFSEF 62