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 665395107 116 RLRWTFKLYDLNGDGRISRGELSEIILAIhelmgrrphqpeDDRKARDQVDRVFRKLDLNQDGIITIEEFLEA 188
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKSL------------GEGLSEEEIDEMIREVDKDGDGKIDFEEFLEL 61

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665395107  86 KAFDVNCNGAISFRDLLVTLSTLLRGS-VYERLRWTFKLYDLNGDGRISRGELSEIILAIHElmgrrphqpeddRKARDQ 164
Cdd:PTZ00184  54 NEVDADGNGTIDFPEFLTLMARKMKDTdSEEEIKEAFKVFDRDGNGFISAAELRHVMTNLGE------------KLTDEE 121

                         90       100
                 ....*....|....*....|.
gi 665395107 165 VDRVFRKLDLNQDGIITIEEF 185
Cdd:PTZ00184 122 VDEMIREADVDGDGQINYEEF 142

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 665395107   117 LRWTFKLYDLNGDGRISRGELSEII 141
Cdd:smart00054   2 LKEAFRLFDKDGDGKIDFEEFKDLL 26

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 665395107 116 RLRWTFKLYDLNGDGRISRGELSEIILAIhelmgrrphqpeDDRKARDQVDRVFRKLDLNQDGIITIEEFLEA 188
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKSL------------GEGLSEEEIDEMIREVDKDGDGKIDFEEFLEL 61

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 665395107  80 YAHYVFKAFDVNCNGAISFRDLLVTLSTLLRGSVYERLRWTFKLYDLNGDGRISRGELSEII 141
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665395107 115 ERLRWTFKLYDLNGDGRISRGELSEIILAIHELM----------------GRRPHQPEDDRKARDQVDRVFRKLDLNQDG 178
Cdd:COG5126    5 RKLDRRFDLLDADGDGVLERDDFEALFRRLWATLfseadtdgdgrisreeFVAGMESLFEATVEPFARAAFDLLDTDGDG 84

                         90
                 ....*....|
gi 665395107 179 IITIEEFLEA 188
Cdd:COG5126   85 KISADEFRRL 94

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 665395107   81 AHYVFKAFDVNCNGAISFRDLLVTLSTLLRGSVYER--LRWTFKLYDLNGDGRISRGELSEIIL 142
Cdd:pfam13499   4 LKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEPLSDeeVEELFKEFDLDKDGRISFEEFLELYS 67

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 665395107  84 VFKAFDVNCNGAISFRDL-------------LVTLSTLLR-------GSV----YERL-----RWT--FKLYDLNGDGRI 132
Cdd:cd16180    5 IFQAVDRDRSGRISAKELqralsngdwtpfsIETVRLMINmfdrdrsGTInfdeFVGLwkyiqDWRrlFRRFDRDRSGSI 84

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665395107 133 SRGELSEIIL--------AIHELMGRRphqpEDDRKARD-QVDR-------------VFRKLDLNQDGIITI--EEFLEA 188
Cdd:cd16180   85 DFNELQNALSsfgyrlspQFVQLLVRK----FDRRRRGSiSFDDfveacvtlkrltdAFRKYDTNRTGYATIsyEDFLTM 160

                 ...
gi 665395107 189 CLK 191
Cdd:cd16180  161 VLS 163

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 665395107  84 VFKAFDVNCNGAIS-------FRDLLVTL---STLLRGSVYERLRWTFKLYDLNGDGRISRGELSEIILAIHE--LMGRR 151
Cdd:cd16178    4 IWQHFDADESGYIEgkeldnfFKDLLKKLgtkDTISADEVQDVKECFMSAYDVTGDGRIQIQELANIILPDDEnfLLFFR 83

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 665395107 152 PHQPEDdrkarDQVD--RVFRKLDLNQDGIITIEEfLEACLKD 192
Cdd:cd16178   84 REEPLD-----SSVEfmRIWRKYDADSSGYISAAE-LKNFLRD 120

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 665395107  76 NSSLYAHYVFKAFDVNCNGAISFRDLLVTLSTLLRGSVYER-------LRWT---FKLYDLNGDGRISRGELSEIiLAIH 145
Cdd:cd16179   92 DSSVEFMKVWREYDKDNSGYIEADELKNFLKHLLKEAKRDNdvsedklIEYTdtiLQLFDRNKDGKLQLSEMARL-LPVK 170

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 665395107 146 ELMGRRPHQPEDDRKARDQVDRVFRKLDLNQDGIITIEEfLEACLKDDL 194
Cdd:cd16179  171 ENFLCRPIFKGAGKLTREDIDRVFALYDRDNNGTIENEE-LTGFLKDLL 218

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 665395107 114 YERLRWTFKLYDLNGDGRISRGELSEIILAIHElmgrrphqpEDDRKARDQVDRVFRKLDLNQDGIITIEEF 185
Cdd:cd16225   33 RKKLKEIFKKVDVNTDGFLSAEELEDWIMEKTQ---------EHFQEAVEENEQIFKAVDTDKDGNVSWEEY 95

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 665395107 121 FKLYDLNGDGRISRGELSEIIlaiHELMGRRPHQPEDDRKARDQVDRVFRKLDLNQDGIITIEEF 185
Cdd:cd15902    5 WMHFDADGNGYIEGKELDSFL---RELLKALNGKDKTDDEVAEKKKEFMEKYDENEDGKIEIREL 66

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.

                          10        20
                  ....*....|....*....|....*
gi 665395107  165 VDRVFRKLDLNQDGIITIEEFLEAC 189
Cdd:pfam00036   2 LKEIFRLFDKDGDGKIDFEEFKELL 26

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).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665395107  72 FPHGNSSLYAHyVFKAFDVNCNGAISFRDLLVTLSTLLRGSVY--ERLRWTfKLYDLNGDGRISRGE-LSEIIlaihelm 148
Cdd:cd16227  153 YPHMHPVLIEQ-TLRDKDKDNDGFISFQEFLGDRAGHEDKEWLlvEKDRFD-EDYDKDGDGKLDGEEiLSWLV------- 223

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 665395107 149 grrphqPEDDRKARDQVDRVFRKLDLNQDGIITIEEFLEA 188
Cdd:cd16227  224 ------PDNEEIAEEEVDHLFASADDDHDDRLSFDEILDH 257

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).

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 665395107 115 ERLRWTFKLYDLNGDGRISRGELSEIILaihelmgrRPHQPEDDRKARDQvdrvFRKLDLNQDGIITIEEFL 186
Cdd:cd16227   36 RRLAVLAKKMDLNDDGFIDRKELKAWIL--------RSFKMLDEEEANER----FEEADEDGDGKVTWEEYL 95

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 665395107  84 VFKAFDVNCNGAISFRDLLVTLSTLLRGSVYERLRWTFKLYDLNGDGRISRGELSEIILAIHELMGRRPHQPEDDRK--A 161
Cdd:cd16226   40 IVDKIDKNGDGFVTEEELKDWIKYVQKKYIREDVDRQWKEYDPNKDGKLSWEEYKKATYGFLDDEEEDDDLHESYKKmiR 119

                         90       100
                 ....*....|....*....|....
gi 665395107 162 RDQvdRVFRKLDLNQDGIITIEEF 185
Cdd:cd16226  120 RDE--RRWKAADQDGDGKLTKEEF 141