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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49065665  22 FTEKEVQQWYKGFIKDCpSGQLDAAGFQKIYKQFFpfgdptkfaTFVFNVFDENKDGRIEFSEFIQALSVTSRGTLDEKL 101
Cdd:COG5126   2 LQRRKLDRRFDLLDADG-DGVLERDDFEALFRRLW---------ATLFSEADTDGDGRISREEFVAGMESLFEATVEPFA 71

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 49065665 102 RWAFKLYDLDNDGYITRNEMLDIVDAIyqmvgntvelpeeeNTPEKRVDRIFAMMDKNADGKLTLQEFQEGSK 174
Cdd:COG5126  72 RAAFDLLDTDGDGKISADEFRRLLTAL--------------GVSEEEADELFARLDTDGDGKISFEEFVAAVR 130

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49065665  22 FTEKEVQQWYKGFIKDCpSGQLDAAGFQKIYKQFFpfgdptkfaTFVFNVFDENKDGRIEFSEFIQALSVTSRGTLDEKL 101
Cdd:COG5126   2 LQRRKLDRRFDLLDADG-DGVLERDDFEALFRRLW---------ATLFSEADTDGDGRISREEFVAGMESLFEATVEPFA 71

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 49065665 102 RWAFKLYDLDNDGYITRNEMLDIVDAIyqmvgntvelpeeeNTPEKRVDRIFAMMDKNADGKLTLQEFQEGSK 174
Cdd:COG5126  72 RAAFDLLDTDGDGKISADEFRRLLTAL--------------GVSEEEADELFARLDTDGDGKISFEEFVAAVR 130

EF-hand domain pair;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 49065665    98 DEKLRWAFKLYDLDNDGYITRNEMLDivdaIYQMVGNTVELPEEEntpekrVDRIFAMMDKNADGKLTLQEFQE 171
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKK----LLRKLEEGEPLSDEE------VEELFKEFDLDKDGRISFEEFLE 64

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 49065665    100 KLRWAFKLYDLDNDGYITRNEMLDIVDAI 128
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49065665  22 FTEKEVQQWYKGFIKDCpSGQLDAAGFQKIYKQFFpfgdptkfaTFVFNVFDENKDGRIEFSEFIQALSVTSRGTLDEKL 101
Cdd:COG5126   2 LQRRKLDRRFDLLDADG-DGVLERDDFEALFRRLW---------ATLFSEADTDGDGRISREEFVAGMESLFEATVEPFA 71

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 49065665 102 RWAFKLYDLDNDGYITRNEMLDIVDAIyqmvgntvelpeeeNTPEKRVDRIFAMMDKNADGKLTLQEFQEGSK 174
Cdd:COG5126  72 RAAFDLLDTDGDGKISADEFRRLLTAL--------------GVSEEEADELFARLDTDGDGKISFEEFVAAVR 130

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
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 49065665  67 FVFNVFDENKDGRIEFSEFIQALSVTSRGTLDEKLRWAFKLYDLDNDGYITRNEMLDIV 125
Cdd:cd00051   4 EAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

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

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 49065665  64 FATFVFNVFDENKDGRIEFSEFIQALSVtsRGTLDEKLRWAFKLYDLDNDGYITRNEMLDIVDAIYQ 130
Cdd:COG5126  70 FARAAFDLLDTDGDGKISADEFRRLLTA--LGVSEEEADELFARLDTDGDGKISFEEFVAAVRDYYT 134

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 49065665  72 FDENKDGRIEFSEFI--QALSVTSRGTLDEKLRWAfKLYDLDNDGYITRNEMLDIVdaiyqmvgntveLPEEENTPEKRV 149
Cdd:cd16227 168 KDKDNDGFISFQEFLgdRAGHEDKEWLLVEKDRFD-EDYDKDGDGKLDGEEILSWL------------VPDNEEIAEEEV 234

                        90
                ....*....|....*....
gi 49065665 150 DRIFAMMDKNADGKLTLQE 168
Cdd:cd16227 235 DHLFASADDDHDDRLSFDE 253

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 49065665  73 DENKDGRIEFSEFIQALSVTSRGT------LDEKLRWAfKLYDLDNDGYITRNEMLDIVDaiyqmvgntvelPEEENTPE 146
Cdd:cd15899 170 DKNGDGFISLEEFISDPYSADENEeepewvKVEKERFV-ELRDKDKDGKLDGEELLSWVD------------PSNQEIAL 236

                        90       100
                ....*....|....*....|..
gi 49065665 147 KRVDRIFAMMDKNADGKLTLQE 168
Cdd:cd15899 237 EEAKHLIAESDENKDGKLSPEE 258

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 49065665  72 FDENKDGRIEFSEFIQALSVTSRGTL--------DEKLRWAFKLYDLDNDGYITRNEMLDIVDAIYQmvgnTVELPEEEN 143
Cdd:cd16177  55 YDKNADGRIEMAELAQILPTEENFLLcfrqhvgsSSEFMEAWRKYDTDRSGYIEANELKGFLSDLLK----KANRPYDEK 130

                        90       100
                ....*....|....*....|....*
gi 49065665 144 TPEKRVDRIFAMMDKNADGKLTLQE 168
Cdd:cd16177 131 KLQEYTQTILRMFDLNGDGKLGLSE 155

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 49065665  40 SGQLDAAGFQKIYKQFF----PFGDPTKFATFV---FNVFDENKDGRIEFSEFIQALSV------TSRGTLDEKLRW--- 103
Cdd:cd15902 104 SGFIEAKELKGFLKDLLlknkKHVSPPKLDEYTkliLKEFDANKDGKLELDEMAKLLPVqenfllKFQILGAMDLTKedf 183

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 49065665 104 --AFKLYDLDNDGYITRNEMLDIVDAIYQMVGNTVELPEEENTpekrVDRIFAMMDKNADGKL 164
Cdd:cd15902 184 ekVFEHYDKDNNGVIEGNELDALLKDLLEKNKADIDKPDLENF----RDAILRACDKNKDGKI 242

EF-hand, calcium binding motif, found in uncharacterized calglandulin-like proteins; The family corresponds to a group of uncharacterized calglandulin-like proteins. Although their biological function remain unclear, they show high sequence similarity with human calglandulin-like protein GAGLP, which is an ortholog of calglandulin from the venom glands of Bothrops insularis snake. Both GAGLP and calglandulin are putative Ca2+-binding proteins with four EF-hand motifs. However, members in this family contain only three EF-hand motifs. In this point, they may belong to the parvalbumin-like EF-hand family, which is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49065665  81 EFSEFIQalSVTSRGTLDEKLRWAFKLYDLDNDGYITRNEMLDIVDAIyQMVGNTVELPEEEntpekrVDRIFAMMDKNA 160
Cdd:cd16252  21 KFFEYMQ--KFQTSEQQEEAIRKAFQMLDKDKSGFIEWNEIKYILSTV-PSSMPVAPLSDEE------AEAMIQAADTDG 91

                        90
                ....*....|.
gi 49065665 161 DGKLTLQEFQE 171
Cdd:cd16252  92 DGRIDFQEFSD 102

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 49065665    100 KLRWAFKLYDLDNDGYITRNEMLDIVDAI 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 49065665  26 EVQQWYKGFIKDCpSGQLDAAGFQKIYKQffpfGDPTKFAT----FVFNVFDENKDGRIEFSEFIQalsvtsrgtLDEKL 101
Cdd:cd16180   1 ELRRIFQAVDRDR-SGRISAKELQRALSN----GDWTPFSIetvrLMINMFDRDRSGTINFDEFVG---------LWKYI 66

                        90       100       110
                ....*....|....*....|....*....|...
gi 49065665 102 R-W--AFKLYDLDNDGYITRNEMldiVDAIYQM 131
Cdd:cd16180  67 QdWrrLFRRFDRDRSGSIDFNEL---QNALSSF 96

EF-hand, calcium binding motif, found in peflin and similar proteins; Peflin, also termed penta-EF hand (PEF) protein with a long N-terminal hydrophobic domain, or penta-EF hand domain-containing protein 1, is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. In lower vertebrates, peflin may interact with transient receptor potential N (TRPN1), suggesting a potential role of peflin in fast transducer channel adaptation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49065665  26 EVQQWYKGFIKDcPSGQLDAAGFQkiykQFFPFGDPTKFA----TFVFNVFDENKDGRIEFSEFiQALSvtsrgTLDEKL 101
Cdd:cd16184   1 EVQQWFQAVDRD-RSGKISAKELQ----QALVNGNWSHFNdetcRLMIGMFDKDKSGTIDIYEF-QALW-----NYIQQW 69

                        90       100
                ....*....|....*....|
gi 49065665 102 RWAFKLYDLDNDGYITRNEM 121
Cdd:cd16184  70 KQVFQQFDRDRSGSIDENEL 89

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 49065665 105 FKLYDLDNDGYITRNEMLDIVdaiyqmvgntvelpEEENTPEKRVDRIFAMMDKNADGKLTLQEF 169
Cdd:cd00052   5 FRSLDPDGDGLISGDEARPFL--------------GKSGLPRSVLAQIWDLADTDKDGKLDKEEF 55

EF-hand-like motif found in the dystrophins subfamily; This dystrophins subfamily includes dystrophin and its two paralogs, utrophin and DRP-2. Dystrophin is a large, submembrane cytoskeletal protein that is the main component of the dystrophin-glycoprotein complex (DGC) in skeletal muscle. It links the transmembrane DGC to the actin cytoskeleton through binding strongly to the cytoplasmic tail of beta-dystroglycan, the transmembrane subunit of a highly O-glycosylated cell-surface protein. Dystrophin also involves in maintaining the structural integrity of cells, as well as in the formation of the blood-brain barrier (BBB). Utrophin, also termed dystrophin-related protein 1 (DRP-1), is an autosomal dystrophin homologue that increases dystrophic muscle function and reduces pathology. It is broadly expressed at both the mRNA and protein levels, and occurs in the cerebrovascular endothelium. Utrophin forms the utrophin-glycoprotein complex (UGC) by interacting with the dystroglycans (DGs) and the sarcoglycan-dystroglycans, sarcoglycans and sarcospan (SG-SSPN) subcomplex. It may act as a scaffolding protein that stabilizes lipid microdomains and clusters mechanosensitive channel subunits, and link the F-actin cytoskeleton to the cell membrane via the associated glycoprotein complex. DRP-2 is mainly expressed in the vertebrate central nervous system (CNS). It is associated with brain membrane fractions and highly enriched in the postsynaptic density. DRP-2 plays a role in the organization of central cholinergic synapses. It interacts with dystroglycan and L-Periaxin to form a transmembrane complex, which plays a role in Schwann cell-basal lamina interactions and in the regulation of the terminal stages of myelination. The dystrophins subfamily has been characterized by a compact cluster of domains comprising a WW domain, four EF-hand-like motifs and a ZZ-domain, followed by two syntrophin binding sites (SBSs) and a looser region with two coiled-coils.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|..
gi 49065665  67 FVFNVFDENKDGRIEFSEFIQALSVTSRGTLDEKLRWAFKLYDlDNDGYITR 118
Cdd:cd16242  58 WLLNVYDSGRSGKIRVLSFKVGLVLLCNAHLEEKYRYLFSLIA-DPNGCVDQ 108

EF-hand, extracellular calcium-binding (EC) motif, found in secreted protein acidic and rich in cysteine (SPARC)-like proteins; The SPARC protein family represents a diverse group of proteins that share a follistatin-like (FS) domain and an extracellular calcium-binding (EC) domain with two EF-hand motifs. It includes SPARC (for secreted protein acidic and rich in cysteine, also termed osteonectin/ON, or basement-membrane protein 40/BM-40), SPARC-like protein 1 (for secreted protein, acidic and rich in cysteines-like 1/ SPARCL1, also termed high endothelial venule protein/Hevi, or MAST 9, or SC-1, or RAGS-1, or QR1, or ECM 2), testicans 1, 2, and 3 (also termed SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycans, or SPOCK), secreted modular calcium-binding protein SMOC-1 (also termed SPARC-related modular calcium-binding protein 1) and SMOC-2 (also termed SPARC-related modular calcium-binding protein 2, or smooth muscle-associated protein 2/SMAP-2), follistatin-related protein 1 (FRP-1, also termed follistatin-like protein 1/fstl-1, TSC-36/Flik, TGF-beta inducible protein). The SPARC proteins have been implicated in modulating cell interaction with the extracellular milieu, including regulation of extracellular matrix assembly and deposition, counter-adhesion, effects on extracellular protease activity, and modulation of growth factor/cytokine signaling pathways, as well as in development and disease.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 49065665  76 KDGRIEFSEFIQALSVTSRgtlDEKLRWAFKLYDLDNDGYITRNEMLDIVdaiYQMVgntvelpeeenTPEKRVDRIFAM 155
Cdd:cd00252  25 ENRSYDNNKRGHDLSGTMR---KEIAQWEFDNLDNNKDGKLDKRELAPFR---APLM-----------PLEHCARGFFES 87

                        90
                ....*....|....
gi 49065665 156 MDKNADGKLTLQEF 169
Cdd:cd00252  88 CDLNKDKKISLQEW 101

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 49065665   100 KLRWAFKLYDLDNDGYITRNEMLDIV 125
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELL 26

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 49065665    40 SGQLDAAGFQKIYKQFFPFGDPTK-FATFVFNVFDENKDGRIEFSEFIQALS 90
Cdd:pfam13499  16 DGYLDVEELKKLLRKLEEGEPLSDeEVEELFKEFDLDKDGRISFEEFLELYS 67

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 49065665  72 FDENKDGRIEFSEFIQALSVTSRGTL--------DEKLRWAFKLYDLDNDGYITRNEMLDIVDAIYQMVGNTVElpeeEN 143
Cdd:cd16176  50 YGQSTDGKIGIVELAQILPTEENFLLffrqqlksSEEFMQTWRKYDADHSGFIEADELKSFLKDLLKKANKPFD----ES 125

                        90       100
                ....*....|....*....|....*
gi 49065665 144 TPEKRVDRIFAMMDKNADGKLTLQE 168
Cdd:cd16176 126 KLEEYTHTMLKMFDSNNDGKLGLTE 150

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 49065665  69 FNVFDENKDGRIEFSEFIQA---------LSVTSRGTLDEKL-----RWAFKLYDLDNDGYITRNEMLdivdAIYQmvgn 134
Cdd:cd16227  78 FEEADEDGDGKVTWEEYLADsfgyddednEEMIKDSTEDDLKlleddKEMFEAADLNKDGKLDKTEFS----AFQH---- 149

                        90       100       110
                ....*....|....*....|....*....|....*.
gi 49065665 135 tvelPEE-ENTPEKRVDRIFAMMDKNADGKLTLQEF 169
Cdd:cd16227 150 ----PEEyPHMHPVLIEQTLRDKDKDNDGFISFQEF 181

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 49065665  73 DENKDGRIEFSEFIQALsVTSRGTLDE-----KLRWAFKLY-DLDNDGYITRNEMLDIVdaiyqmvgntveLPEEENTPE 146
Cdd:cd16226 166 DKNKDGFISLEEYIGDM-YRDDDEEEDpdwvkSEREQFKEFrDKNKDGKMDREEVKDWI------------LPEDYDHAE 232

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                ....*....|....*....|..
gi 49065665 147 KRVDRIFAMMDKNADGKLTLQE 168
Cdd:cd16226 233 AEAKHLIYEADDDKDGKLTKEE 254

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 49065665    149 VDRIFAMMDKNADGKLTLQEFQEGSKA 175
Cdd:smart00054   2 LKEAFRLFDKDGDGKIDFEEFKDLLKA 28

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 49065665    68 VFNVFDENKDGRIEFSEFIQALS 90
Cdd:pfam00036   5 IFRLFDKDGDGKIDFEEFKELLK 27