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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 41152283  21 EFTDHELQEWYKGFLKDCpSGHLNVEEFKKIYANFFpygdaskfaEHVFRTFDTNNDGTIDFREFIIALSVTSRGKLEQK 100
Cdd:COG5126   1 DLQRRKLDRRFDLLDADG-DGVLERDDFEALFRRLW---------ATLFSEADTDGDGRISREEFVAGMESLFEATVEPF 70

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 41152283 101 LKWAFSMYDLDGNGYISREEmleivqaiYKMVSSVMKMPEDEstpekrTDKIFRQMDLNNDGKLSLEEFIKGAKS 175
Cdd:COG5126  71 ARAAFDLLDTDGDGKISADE--------FRRLLTALGVSEEE------ADELFARLDTDGDGKISFEEFVAAVRD 131

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 41152283  21 EFTDHELQEWYKGFLKDCpSGHLNVEEFKKIYANFFpygdaskfaEHVFRTFDTNNDGTIDFREFIIALSVTSRGKLEQK 100
Cdd:COG5126   1 DLQRRKLDRRFDLLDADG-DGVLERDDFEALFRRLW---------ATLFSEADTDGDGRISREEFVAGMESLFEATVEPF 70

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 41152283 101 LKWAFSMYDLDGNGYISREEmleivqaiYKMVSSVMKMPEDEstpekrTDKIFRQMDLNNDGKLSLEEFIKGAKS 175
Cdd:COG5126  71 ARAAFDLLDTDGDGKISADE--------FRRLLTALGVSEEE------ADELFARLDTDGDGKISFEEFVAAVRD 131

EF-hand domain pair;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 41152283    98 EQKLKWAFSMYDLDGNGYISREEMLEIVQAIYkmvssvmkmpEDESTPEKRTDKIFRQMDLNNDGKLSLEEFIKGAK 174
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLE----------EGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 41152283   63 KFAEHVFRTFDTNNDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDLDGNGYISREEMleivqaiykmvSSVMKMP--- 139
Cdd:NF041410  27 QFQKQLFAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDEL-----------AAAAPPPppp 95

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 41152283  140 EDESTPEKRTDKIFRQMDLNNDGKLSLEEFIKGAKSDPS 178
Cdd:NF041410  96 PDQAPSTELADDLLSALDTDGDGSISSDELSAGLTSAGS 134

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 41152283  21 EFTDHELQEWYKGFLKDCpSGHLNVEEFKKIYANFFpygdaskfaEHVFRTFDTNNDGTIDFREFIIALSVTSRGKLEQK 100
Cdd:COG5126   1 DLQRRKLDRRFDLLDADG-DGVLERDDFEALFRRLW---------ATLFSEADTDGDGRISREEFVAGMESLFEATVEPF 70

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 41152283 101 LKWAFSMYDLDGNGYISREEmleivqaiYKMVSSVMKMPEDEstpekrTDKIFRQMDLNNDGKLSLEEFIKGAKS 175
Cdd:COG5126  71 ARAAFDLLDTDGDGKISADE--------FRRLLTALGVSEEE------ADELFARLDTDGDGKISFEEFVAAVRD 131

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

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 41152283 100 KLKWAFSMYDLDGNGYISREEMLEIVQAIYkmvssvmkmpedESTPEKRTDKIFRQMDLNNDGKLSLEEFIKGAK 174
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLG------------EGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 41152283   73 DTNNDGTIDFREFIIALSVTSR-GKLEQKLKWAFSMYDLDGNGYISREEMLEIvqaiykMVSSVMKMPEDEstpekrTDK 151
Cdd:PTZ00184  57 DADGNGTIDFPEFLTLMARKMKdTDSEEEIKEAFKVFDRDGNGFISAAELRHV------MTNLGEKLTDEE------VDE 124

                         90       100
                 ....*....|....*....|
gi 41152283  152 IFRQMDLNNDGKLSLEEFIK 171
Cdd:PTZ00184 125 MIREADVDGDGQINYEEFVK 144

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 41152283  40 SGHLNVEEFKKIYANFFPYGDAsKFAEHVFRTFDTNNDGTIDFREFIIALSVtsRGKLEQKLKWAFSMYDLDGNGYISRE 119
Cdd:COG5126  47 DGRISREEFVAGMESLFEATVE-PFARAAFDLLDTDGDGKISADEFRRLLTA--LGVSEEEADELFARLDTDGDGKISFE 123

                        90
                ....*....|
gi 41152283 120 EMLEIVQAIY 129
Cdd:COG5126 124 EFVAAVRDYY 133

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 41152283  26 ELQEWYKGFLKDCpSGHLNVEEFKKIYAN---FFPYGDASKFaehvFRTFDTNNDGTIDFREFiIALSvtsrgKLEQKLK 102
Cdd:cd16185   1 ELRQWFRAVDRDR-SGSIDVNELQKALAGgglLFSLATAEKL----IRMFDRDGNGTIDFEEF-AALH-----QFLSNMQ 69

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 41152283 103 WAFSMYDLDGNGYISREEMLEIVQAI-YKMVSSVMKmpedestpekrtdKIFRQMDLNNDGKLSLEEFI 170
Cdd:cd16185  70 NGFEQRDTSRSGRLDANEVHEALAASgFQLDPPAFQ-------------ALFRKFDPDRGGSLGFDDYI 125

EF-hand-like motif found in the dystrophin/dystrobrevin/dystrotelin family; The dystrophin/dystrobrevin/dystrotelin family has been characterized by a compact cluster of domains comprising four EF-hand-like motifs and a ZZ-domain, followed by a looser region with two coiled-coils. Dystrophin is the founder member of this family. It is a sub-membrane cytoskeletal protein associated with the inner surface membrane. Dystrophin and its close paralog utrophin have a large N-terminal extension of actin-binding CH domains, up to 24 spectrin repeats, and a WW domain. Its further paralog, dystrophin-related protein 2 (DRP-2), retains only two of the spectrin repeats. Dystrophin, utrophin or DRP2 can form the core of a membrane-bound complex consisting of dystroglycan, sarcoglycans and syntrophins, known as the dystrophin-glycoprotein complex (DGC) that plays an important role in brain development and disease, as well as in the prevention of muscle damage. Dystrobrevins, including alpha- and beta-dystrobrevin, lack the large N-terminal extension found in dystrophin, but alpha-dystrobrevin has a characteristic C-terminal extension. Dystrobrevins are part of the DGC. They physically associate with members of the dystrophin family and with the syntrophins through their homologous C-terminal coiled coil motifs. In contrast, dystrotelins lack both the large N-terminal extension found in dystrophin and the obvious syntrophin-binding sites (SBSs). Dystrotelins are not critical for mammalian development. They may be involved in other forms of cytokinesis. Moreover, dystrotelin is unable to heterodimerize with members of the dystrophin or dystrobrevin families, or to homodimerize.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 41152283  71 TFDTNNDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDlDGNGYISREEMLEIVQAIYKMVS 133
Cdd:cd15901  62 LYDRNRTGCIRLLSVKIALITLCAASLLDKYRYLFGQLA-DSSGFISRERLTQFLQDLLQIPD 123

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

                           10        20
                   ....*....|....*....|....*....
gi 41152283    100 KLKWAFSMYDLDGNGYISREEMLEIVQAI 128
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

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 41152283  26 ELQEWYKGFLKDCpSGHLNVEEFKKIYANffpyGDASKFAEHV----FRTFDTNNDGTIDFREFIialsvtsrgKLEQKL 101
Cdd:cd16180   1 ELRRIFQAVDRDR-SGRISAKELQRALSN----GDWTPFSIETvrlmINMFDRDRSGTINFDEFV---------GLWKYI 66

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 41152283 102 K-W--AFSMYDLDGNGYISREEMLEIVQAI-YKMVSSVmkmpedestpekrTDKIFRQMDLNNDGKLSLEEFI 170
Cdd:cd16180  67 QdWrrLFRRFDRDRSGSIDFNELQNALSSFgYRLSPQF-------------VQLLVRKFDRRRRGSISFDDFV 126

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 41152283  72 FDTNNDGTIDFRE----------FIIALSVTSRGKLEQKLKWAFSMYDLDGNGYISREEMleivQAIYKMVSSVMKMPED 141
Cdd:cd15902  53 YDENEDGKIEIRElanilpteenFLLLFRREQPLISSVEFMKIWRKYDTDGSGFIEAKEL----KGFLKDLLLKNKKHVS 128

                        90       100       110
                ....*....|....*....|....*....|
gi 41152283 142 ESTPEKRTDKIFRQMDLNNDGKLSLEEFIK 171
Cdd:cd15902 129 PPKLDEYTKLILKEFDANKDGKLELDEMAK 158

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 41152283   18 ENTEFTDHELQEWYKGF-LKDCP-SGHLNVEEFKkiyANFFPYGDASKfAEHVFRTF---DTNNDGTIDFREF--IIALS 90
Cdd:PTZ00183   7 ERPGLTEDQKKEIREAFdLFDTDgSGTIDPKELK---VAMRSLGFEPK-KEEIKQMIadvDKDGSGKIDFEEFldIMTKK 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 41152283   91 VTSRGKLEQKLKwAFSMYDLDGNGYISREEMLEIVQAIykmvssvmkmpedestPEKRTDKIFRQM----DLNNDGKLSL 166
Cdd:PTZ00183  83 LGERDPREEILK-AFRLFDDDKTGKISLKNLKRVAKEL----------------GETITDEELQEMideaDRNGDGEISE 145

                        170
                 ....*....|.
gi 41152283  167 EEFIKGAKSDP 177
Cdd:PTZ00183 146 EEFYRIMKKTN 156

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 41152283  73 DTNNDGTIDFREFIIALsVTSRGKLEQkLKW------AFSMY-DLDGNGYISREEMLEIVqaiykmvssvmkMPEDESTP 145
Cdd:cd16226 166 DKNKDGFISLEEYIGDM-YRDDDEEED-PDWvksereQFKEFrDKNKDGKMDREEVKDWI------------LPEDYDHA 231

                        90       100
                ....*....|....*....|...
gi 41152283 146 EKRTDKIFRQMDLNNDGKLSLEE 168
Cdd:cd16226 232 EAEAKHLIYEADDDKDGKLTKEE 254

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 41152283 105 FSMYDLDGNGYISREEMLEIvqaiykMVSSvmKMPEDEstpekrTDKIFRQMDLNNDGKLSLEEFI 170
Cdd:cd00052   5 FRSLDPDGDGLISGDEARPF------LGKS--GLPRSV------LAQIWDLADTDKDGKLDKEEFA 56

EF-hand, extracellular calcium-binding (EC) motif, found in secreted modular calcium-binding protein SMOC-1, SMOC-2, and similar proteins; SMOC proteins corresponds to a group matricellular proteins that are involved in direct or indirect modulation of growth factor signaling pathways and play diverse roles in physiological processes involving extensive tissue remodeling, migration, proliferation, and angiogenesis. They may mediate intercellular signaling and cell type-specific differentiation during gonad and reproductive tract development. SMOC-1 is localized in basement membranes. Its mutations have been found to be associated with individuals with Warrdenburg Anopthalmia Syndrome. SMOC-2 is ubiquitously expressed and is involved in angiogenesis and the regulation of cell cycle progression. It enhances the angiogenic effect of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). It has also been implicated in generalized vitiligo. SMOC proteins consist of a follistatin-like (FS) domain, two thyroglobulin-like (TY) domains, a novel domain conserved only in SMOC proteins, and an extracellular calcium-binding (EC) domain with two EF-hand calcium-binding motifs.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 41152283  98 EQKLKWAFSMYDLDGNGYISREEmleiVQAIYKMVSSVMKmpedestPEKRTDKIFRQMDLNNDGKLSLEEFIK 171
Cdd:cd16234  38 EQVLDWKFSQLDKNKNGVLERKE----WKPFKRLLKKAVK-------PKKCARKFPKYCDVNKDKKISLTEWLN 100

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 41152283  70 RTFDTNNDGTIDFREFIiALSVTSRGKlEQKLKWAFS-------MYDLDGNGYISREEMLEIVqaiykmvssvmkMPEDE 142
Cdd:cd15899 167 EDLDKNGDGFISLEEFI-SDPYSADEN-EEEPEWVKVekerfveLRDKDKDGKLDGEELLSWV------------DPSNQ 232

                        90       100
                ....*....|....*....|....*....
gi 41152283 143 STPEKRTDKIFRQMDLNNDGKLSLEEFIK 171
Cdd:cd15899 233 EIALEEAKHLIAESDENKDGKLSPEEILD 261

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 41152283  12 MLQDLRENTEFTDHELQEWYKGFLKDcPSGHLNVEEFKKIYANFF----PYGDASKFAEHV---FRTFDTNNDGTIDFRE 84
Cdd:cd15902  77 LLLFRREQPLISSVEFMKIWRKYDTD-GSGFIEAKELKGFLKDLLlknkKHVSPPKLDEYTkliLKEFDANKDGKLELDE 155

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 41152283  85 FIIALSV------TSRGKLEQKLKW-----AFSMYDLDGNGYISREEMLEIVQAIYKMVSSVMKMPEDestpEKRTDKIF 153
Cdd:cd15902 156 MAKLLPVqenfllKFQILGAMDLTKedfekVFEHYDKDNNGVIEGNELDALLKDLLEKNKADIDKPDL----ENFRDAIL 231

                       170
                ....*....|....*
gi 41152283 154 RQMDLNNDGKLSLEE 168
Cdd:cd15902 232 RACDKNKDGKIQKTE 246

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 41152283  14 QDLRENTEFtdheLQEWYKgFLKDcPSGHLNVEEFKKIYANFF-----PYgDASKFAEH---VFRTFDTNNDGTIDFREF 85
Cdd:cd16176  79 QQLKSSEEF----MQTWRK-YDAD-HSGFIEADELKSFLKDLLkkankPF-DESKLEEYthtMLKMFDSNNDGKLGLTEM 151

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 41152283  86 IIALSVTSRGKLE--------QKLKWAFSMYDLDGNGYISREEM 121
Cdd:cd16176 152 ARLLPVQENFLLKfqgvkmcgKEFNKIFELYDQDGNGYIDENEL 195

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 41152283  28 QEW---YKGFLKDcPSGHLNVEEFKKIYANFfPYGDASKFAEHVFRTFDTNNDGTIDFREFIIALSVTsrgkleQKLKWA 104
Cdd:cd16183  67 TDWqncFRSFDRD-NSGNIDKNELKQALTSF-GYRLSDQFYDILVRKFDRQGRGTIAFDDFIQCCVVL------QTLTDS 138

                        90       100
                ....*....|....*....|...
gi 41152283 105 FSMYDLDGNGYI--SREEMLEIV 125
Cdd:cd16183 139 FRRYDTDQDGWIqiSYEQFLEMV 161

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 41152283  15 DLRENTEFTDHELQEWYKGFLKDCP---------SGHLNVEEFkkiyANFFPYGDA---SKFA-EHVFRTFDTNNDGTID 81
Cdd:cd16224 104 DYDEDTVLDDEEEESFRQLHLKDKKrfdkantdgGPGLNLTEF----IAFEHPEEVdymTEFViQEALEEHDKDGDGFIS 179

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 41152283  82 FREFIIALSVTSRGK------LEQKLKWAfSMYDLDGNGYISREEMLEIVqaiykmvssvmkMPEDESTPEKRTDKIFRQ 155
Cdd:cd16224 180 LEEFLGDYRKDPTANedpewiIVEKDRFV-NDYDKDNDGKLDPQELLPWV------------VPNNYGIAQEEALHLIDE 246

                       170
                ....*....|....*.
gi 41152283 156 MDLNNDGKLSLEEFIK 171
Cdd:cd16224 247 MDLNGDGRLSEEEILE 262

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 41152283    39 PSGHLNVEEFKKIYANFFPYGDASKFAEHVFRTFDTNNDGTIDFREFIIAL 89
Cdd:pfam13833   1 EKGVITREELKRALALLGLKDLSEDEVDILFREFDTDGDGYISFDEFCVLL 51

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 41152283  63 KFAEHV---FRTFDTNNDGTIDFREFIIALSVTSRGKL--------EQKLKWAFSMYDLDGNGYISREEMLEIVQAIYKM 131
Cdd:cd16177  43 NFGEKMkefMQKYDKNADGRIEMAELAQILPTEENFLLcfrqhvgsSSEFMEAWRKYDTDRSGYIEANELKGFLSDLLKK 122

                        90       100       110       120
                ....*....|....*....|....*....|....*....|
gi 41152283 132 VSSvmkmPEDESTPEKRTDKIFRQMDLNNDGKLSLEEFIK 171
Cdd:cd16177 123 ANR----PYDEKKLQEYTQTILRMFDLNGDGKLGLSEMAR 158

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

                           10        20
                   ....*....|....*....|...
gi 41152283     68 VFRTFDTNNDGTIDFREFIIALS 90
Cdd:smart00054   5 AFRLFDKDGDGKIDFEEFKDLLK 27

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

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 41152283 104 AFSMYDLDGNGYISREEMLEIVQAIYKMVSSVMKmpedeSTPEKRTDKIFRQMD---------LNNDGKLSLEEFIK 171
Cdd:cd15900   5 AFKMFDLDGDGELDKEEFNKVQSIIRSQTSVGQR-----HRDHTNGESTKLGMNstlaryffgKDGKQKLSIEKFLE 76

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        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 41152283 111 DGNGY-ISREEMLEIVQaiyKMVSSVMKMPEDESTpekrTDKIFRQMDLNNDGKLSLEEFI 170
Cdd:cd00213  21 EGDKDtLSKKELKELLE---TELPNFLKNQKDPEA----VDKIMKDLDVNKDGKVDFQEFL 74

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

                           10        20
                   ....*....|....*....|....*.
gi 41152283    150 DKIFRQMDLNNDGKLSLEEFIKGAKS 175
Cdd:smart00054   3 KEAFRLFDKDGDGKIDFEEFKDLLKA 28

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 41152283   112 GNGYISREEMLEIvqaiykmvSSVMKMPEdesTPEKRTDKIFRQMDLNNDGKLSLEEFI 170
Cdd:pfam13833   1 EKGVITREELKRA--------LALLGLKD---LSEDEVDILFREFDTDGDGYISFDEFC 48

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 41152283  60 DASKFAEHVFRTFDTNNDGTIDFRE----------FIIALSVTSrgKLEQKLKW--AFSMYDLDGNGYISREEMLEIVQA 127
Cdd:cd16179  46 ALEELKEEFMEAYDENQDGRIDIRElaqllpteenFLLLFRRDN--PLDSSVEFmkVWREYDKDNSGYIEADELKNFLKH 123

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 41152283 128 IYKMvssvmKMPEDESTPEK---RTDKIFRQMDLNNDGKLSLEEFIK 171
Cdd:cd16179 124 LLKE-----AKRDNDVSEDKlieYTDTILQLFDRNKDGKLQLSEMAR 165

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 41152283  99 QKLKWAFSMYDLDGNGYISREEMLEIVQAIYKMVSsvmkmpedestpEKRTDKIFRQMDLNNDGKLSLEEFIKG 172
Cdd:cd16226  35 ERLGIIVDKIDKNGDGFVTEEELKDWIKYVQKKYI------------REDVDRQWKEYDPNKDGKLSWEEYKKA 96

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 41152283  36 KDCPSGHLNVEEFKKI----YANFFPYGDASKFAEHVFRTFDTNNDGTIDFREFIIAL 89
Cdd:cd00213  20 KEGDKDTLSKKELKELleteLPNFLKNQKDPEAVDKIMKDLDVNKDGKVDFQEFLVLI 77

EF-hand domain;

                          10        20
                  ....*....|....*....|....
gi 41152283    66 EHVFRTFDTNNDGTIDFREFIIAL 89
Cdd:pfam13405   3 REAFKLFDKDGDGKISLEELRKAL 26