NCBI Conserved Domain Search

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

Pssm-ID: 444056 [Multi-domain] Cd Length: 137 Bit Score: 85.61 E-value: 1.21e-21

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  21 DFTEHEIQEWYKGFLRDCpSGHLSMEEFKKIYGNFFpygdaskfaEHVFRTFDANGDGTIDFREFIIALSVTSRGKLEQK 100
Cdd:COG5126   1 DLQRRKLDRRFDLLDADG-DGVLERDDFEALFRRLW---------ATLFSEADTDGDGRISREEFVAGMESLFEATVEPF 70

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 98985785 101 LKWAFSMYDLDGNGYISKAEmleivqaiYKMVSSVMKMPEDEstpekrTEKIFRQMDTNRDGKLSLEEFIRGAKS 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.

Pssm-ID: 238008 [Multi-domain] Cd Length: 63 Bit Score: 71.81 E-value: 3.94e-17

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 98985785  65 AEHVFRTFDANGDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDLDGNGYISKAEMLEIVQ 126
Cdd:cd00051   2 LREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

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.

Pssm-ID: 238008 [Multi-domain] Cd Length: 63 Bit Score: 71.04 E-value: 8.79e-17

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 98985785 100 KLKWAFSMYDLDGNGYISKAEMLEIVQAIYkmvssvmkmpedESTPEKRTEKIFRQMDTNRDGKLSLEEFIRGAK 174
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLG------------EGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

calmodulin; Provisional

Pssm-ID: 185504 [Multi-domain] Cd Length: 149 Bit Score: 63.24 E-value: 5.23e-13

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785   73 DANGDGTIDFREFIIALSVTSR-GKLEQKLKWAFSMYDLDGNGYISKAEMLEIvqaiykMVSSVMKMPEDEstpekrTEK 151
Cdd:PTZ00184  57 DADGNGTIDFPEFLTLMARKMKdTDSEEEIKEAFKVFDRDGNGFISAAELRHV------MTNLGEKLTDEE------VDE 124

                         90       100
                 ....*....|....*....|
gi 98985785  152 IFRQMDTNRDGKLSLEEFIR 171
Cdd:PTZ00184 125 MIREADVDGDGQINYEEFVK 144

EF-hand domain pair;

Pssm-ID: 463900 [Multi-domain] Cd Length: 67 Bit Score: 59.57 E-value: 1.86e-12

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 98985785    98 EQKLKWAFSMYDLDGNGYISKAEMLEIVQAIYkmvssvmkmpEDESTPEKRTEKIFRQMDTNRDGKLSLEEFIRGAK 174
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLE----------EGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

XopAW family type III secretion system calcium-binding effector;

Pssm-ID: 469301 [Multi-domain] Cd Length: 227 Bit Score: 60.46 E-value: 2.24e-11

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785   63 KFAEHVFRTFDANGDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDLDGNGYISKAEMleivqaiykmvSSVMKMP--- 139
Cdd:NF041410  27 QFQKQLFAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDEL-----------AAAAPPPppp 95

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 98985785  140 EDESTPEKRTEKIFRQMDTNRDGKLSLEEFIRGAKSDPS 178
Cdd:NF041410  96 PDQAPSTELADDLLSALDTDGDGSISSDELSAGLTSAGS 134

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

Pssm-ID: 444056 [Multi-domain] Cd Length: 137 Bit Score: 58.65 E-value: 2.95e-11

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  17 LESTDFTEHEIQEWYKGFLRDCP--SGHLSMEEFKKIYGNFFPYGDAsKFAEHVFRTFDANGDGTIDFREFIIALSVtsR 94
Cdd:COG5126  22 LERDDFEALFRRLWATLFSEADTdgDGRISREEFVAGMESLFEATVE-PFARAAFDLLDTDGDGKISADEFRRLLTA--L 98

                        90       100       110
                ....*....|....*....|....*....|....*
gi 98985785  95 GKLEQKLKWAFSMYDLDGNGYISKAEMLEIVQAIY 129
Cdd:COG5126  99 GVSEEEADELFARLDTDGDGKISFEEFVAAVRDYY 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).

Pssm-ID: 320060 [Multi-domain] Cd Length: 163 Bit Score: 54.91 E-value: 8.76e-10

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  26 EIQEWYKGFLRDCpSGHLSMEEFKKI---YGNFFPYGDASKFaehvFRTFDANGDGTIDFREFiIALSvtsrgKLEQKLK 102
Cdd:cd16185   1 ELRQWFRAVDRDR-SGSIDVNELQKAlagGGLLFSLATAEKL----IRMFDRDGNGTIDFEEF-AALH-----QFLSNMQ 69

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785 103 WAFSMYDLDGNGYISKAEMLEIVQAI-YKMVSSVMKmpedestpekrteKIFRQMDTNRDGKLSLEEFIR 171
Cdd:cd16185  70 NGFEQRDTSRSGRLDANEVHEALAASgFQLDPPAFQ-------------ALFRKFDPDRGGSLGFDDYIE 126

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).

Pssm-ID: 320025 [Multi-domain] Cd Length: 263 Bit Score: 50.78 E-value: 8.61e-08

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  41 GHLSMEEFKKIYGnffPYGDASKFA---EHVFRTFDANGDGTIDFREFI--IALSVTSRGKLEQKLKWAFSmYDLDGNGY 115
Cdd:cd16227 137 GKLDKTEFSAFQH---PEEYPHMHPvliEQTLRDKDKDNDGFISFQEFLgdRAGHEDKEWLLVEKDRFDED-YDKDGDGK 212

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 98985785 116 ISKAEMLEIVqaiykmvssvmkMPEDESTPEKRTEKIFRQMDTNRDGKLSLEEFI 170
Cdd:cd16227 213 LDGEEILSWL------------VPDNEEIAEEEVDHLFASADDDHDDRLSFDEIL 255

EF-hand domain pair;

Pssm-ID: 463900 [Multi-domain] Cd Length: 67 Bit Score: 44.17 E-value: 1.18e-06

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 98985785    68 VFRTFDANGDGTIDFREFIIALSVTSRGK--LEQKLKWAFSMYDLDGNGYISKAEMLEIVQ 126
Cdd:pfam13499   7 AFKLLDSDGDGYLDVEELKKLLRKLEEGEplSDEEVEELFKEFDLDKDGRISFEEFLELYS 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+.

Pssm-ID: 320055 [Multi-domain] Cd Length: 164 Bit Score: 45.98 E-value: 1.53e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  26 EIQEWYKGFLRDCpSGHLSMEEFKKIYGNffpyGDASKFAEHV----FRTFDANGDGTIDFREFIialsvtsrgKLEQKL 101
Cdd:cd16180   1 ELRRIFQAVDRDR-SGRISAKELQRALSN----GDWTPFSIETvrlmINMFDRDRSGTINFDEFV---------GLWKYI 66

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 98985785 102 K-W--AFSMYDLDGNGYISKAEMLEIVQAI-YKMVSSVmkmpedestpekrTEKIFRQMDTNRDGKLSLEEFIR 171
Cdd:cd16180  67 QdWrrLFRRFDRDRSGSIDFNELQNALSSFgYRLSPQF-------------VQLLVRKFDRRRRGSISFDDFVE 127

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.

Pssm-ID: 320079 [Multi-domain] Cd Length: 261 Bit Score: 45.86 E-value: 3.60e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  64 FAEHVFRTFDANGDGTIDFREFIIALSVTSRGKLEQKLKWA-----------FSMYDLDGNGYISKAEM-------LEIV 125
Cdd:cd16179 142 YTDTILQLFDRNKDGKLQLSEMARLLPVKENFLCRPIFKGAgkltredidrvFALYDRDNNGTIENEELtgflkdlLELV 221

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 98985785 126 QAIYkmvssvmkmpeDESTPEKRTEKIFRQMDTNRDGKLSLEE 168
Cdd:cd16179 222 QEDY-----------DEQDLEEFKEIILRGWDFNNDGKISRKE 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.

Pssm-ID: 320021 [Multi-domain] Cd Length: 267 Bit Score: 43.97 E-value: 1.68e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  70 RTFDANGDGTIDFREFIiALSVTSRGKlEQKLKWAFS-------MYDLDGNGYISKAEMLEIVqaiykmvssvmkMPEDE 142
Cdd:cd15899 167 EDLDKNGDGFISLEEFI-SDPYSADEN-EEEPEWVKVekerfveLRDKDKDGKLDGEELLSWV------------DPSNQ 232

                        90       100
                ....*....|....*....|....*.
gi 98985785 143 STPEKRTEKIFRQMDTNRDGKLSLEE 168
Cdd:cd15899 233 EIALEEAKHLIAESDENKDGKLSPEE 258

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.

Pssm-ID: 319999 Cd Length: 163 Bit Score: 43.03 E-value: 1.74e-05

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 98985785  71 TFDANGDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDlDGNGYISKAEMLEIVQAIYKMVS 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.

Pssm-ID: 197492 [Multi-domain] Cd Length: 29 Bit Score: 40.05 E-value: 1.78e-05

                           10        20
                   ....*....|....*....|....*....
gi 98985785    100 KLKWAFSMYDLDGNGYISKAEMLEIVQAI 128
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

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.

Pssm-ID: 320075 [Multi-domain] Cd Length: 254 Bit Score: 43.50 E-value: 2.45e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  63 KFAEHVFRTFDANGDGTIDFREFIIALSV------TSRGKLEQKLKW-----AFSMYDLDGNGYISKAEMLEIVQAIYKM 131
Cdd:cd15902 134 EYTKLILKEFDANKDGKLELDEMAKLLPVqenfllKFQILGAMDLTKedfekVFEHYDKDNNGVIEGNELDALLKDLLEK 213

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 98985785 132 VSSVMKMPEDestpEKRTEKIFRQMDTNRDGKLSLEE 168
Cdd:cd15902 214 NKADIDKPDL----ENFRDAILRACDKNKDGKIQKTE 246

centrin; Provisional

Pssm-ID: 185503 [Multi-domain] Cd Length: 158 Bit Score: 41.98 E-value: 3.94e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785   18 ESTDFTEHEIQEWYKGF-LRDCP-SGHLSMEEFKKIYGNFfpyGDASKfAEHVFRTF---DANGDGTIDFREF--IIALS 90
Cdd:PTZ00183   7 ERPGLTEDQKKEIREAFdLFDTDgSGTIDPKELKVAMRSL---GFEPK-KEEIKQMIadvDKDGSGKIDFEEFldIMTKK 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785   91 VTSRGKLEQKLKwAFSMYDLDGNGYISkaemleivqaiYKMVSSVMKMPEDESTPEKRTEKIFRQmDTNRDGKLSLEEFI 170
Cdd:PTZ00183  83 LGERDPREEILK-AFRLFDDDKTGKIS-----------LKNLKRVAKELGETITDEELQEMIDEA-DRNGDGEISEEEFY 149


                 ....*..
gi 98985785  171 RGAKSDP 177
Cdd:PTZ00183 150 RIMKKTN 156

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.

Pssm-ID: 320075 [Multi-domain] Cd Length: 254 Bit Score: 42.34 E-value: 5.88e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  45 MEEFKKIYGNFFPYGDASKFAEHVFRTFDANGDGTIDFRE----------FIIALSVTSRGKLEQKLKWAFSMYDLDGNG 114
Cdd:cd15902  26 RELLKALNGKDKTDDEVAEKKKEFMEKYDENEDGKIEIRElanilpteenFLLLFRREQPLISSVEFMKIWRKYDTDGSG 105

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 98985785 115 YISKAEMleivQAIYKMVSSVMKMPEDESTPEKRTEKIFRQMDTNRDGKLSLEEFIR 171
Cdd:cd15902 106 FIEAKEL----KGFLKDLLLKNKKHVSPPKLDEYTKLILKEFDANKDGKLELDEMAK 158

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.

Pssm-ID: 238009 [Multi-domain] Cd Length: 67 Bit Score: 39.51 E-value: 7.67e-05

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 98985785 105 FSMYDLDGNGYISKAEMLEIvqaiykMVSSvmKMPEDEstpekrTEKIFRQMDTNRDGKLSLEEFI 170
Cdd:cd00052   5 FRSLDPDGDGLISGDEARPF------LGKS--GLPRSV------LAQIWDLADTDKDGKLDKEEFA 56

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+.

Pssm-ID: 320055 [Multi-domain] Cd Length: 164 Bit Score: 40.97 E-value: 9.75e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  34 FLRDcPSGHLSMEEFKKIYgnffpygdasKFAE---HVFRTFDANGDGTIDFREFIIALsvTSRG-KL-EQKLKWAFSMY 108
Cdd:cd16180  46 FDRD-RSGTINFDEFVGLW----------KYIQdwrRLFRRFDRDRSGSIDFNELQNAL--SSFGyRLsPQFVQLLVRKF 112

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 98985785 109 DLDGNGYISKAEMLEIvqaiykmVSSVMKMpedestpekrTEKiFRQMDTNRDG--KLSLEEFI 170
Cdd:cd16180 113 DRRRRGSISFDDFVEA-------CVTLKRL----------TDA-FRKYDTNRTGyaTISYEDFL 158

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.

Pssm-ID: 320059 [Multi-domain] Cd Length: 165 Bit Score: 41.10 E-value: 1.04e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  26 EIQEWYKGFLRDcPSGHLSMEEFKKIYGNffpyGDASKFAEH----VFRTFDANGDGTIDFREFiialsvTSRGKLEQKL 101
Cdd:cd16184   1 EVQQWFQAVDRD-RSGKISAKELQQALVN----GNWSHFNDEtcrlMIGMFDKDKSGTIDIYEF------QALWNYIQQW 69

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785 102 KWAFSMYDLDGNGYISKAEMleiVQAIYKM--------VSSVM---------KMPEDE----STPEKRTEKIFRQMDTNR 160
Cdd:cd16184  70 KQVFQQFDRDRSGSIDENEL---HQALSQMgyrlspqfVQFLVskydprarrSLTLDQfiqvCVQLQSLTDAFRQRDTQM 146

                       170
                ....*....|..
gi 98985785 161 DG--KLSLEEFI 170
Cdd:cd16184 147 TGtiTISYEDFL 158

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.

Pssm-ID: 320058 [Multi-domain] Cd Length: 165 Bit Score: 40.70 E-value: 1.16e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  27 IQEW---YKGFLRDcPSGHLSMEEFKKIYGNFfPYGDASKFAEHVFRTFDANGDGTIDFREFIIALSVTsrgkleQKLKW 103
Cdd:cd16183  66 ITDWqncFRSFDRD-NSGNIDKNELKQALTSF-GYRLSDQFYDILVRKFDRQGRGTIAFDDFIQCCVVL------QTLTD 137

                        90       100
                ....*....|....*....|....
gi 98985785 104 AFSMYDLDGNGYI--SKAEMLEIV 125
Cdd:cd16183 138 SFRRYDTDQDGWIqiSYEQFLEMV 161

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.

Pssm-ID: 320009 Cd Length: 107 Bit Score: 38.89 E-value: 2.16e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  89 LSVTSRgklEQKLKWAFSMYDLDGNGYISKAEMLEIVQaiykmvssvMKMPedestPEKRTEKIFRQMDTNRDGKLSLEE 168
Cdd:cd00252  38 LSGTMR---KEIAQWEFDNLDNNKDGKLDKRELAPFRA---------PLMP-----LEHCARGFFESCDLNKDKKISLQE 100


                ..
gi 98985785 169 FI 170
Cdd:cd00252 101 WL 102

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.

Pssm-ID: 238131 [Multi-domain] Cd Length: 88 Bit Score: 38.62 E-value: 2.26e-04

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 98985785 111 DGNGY-ISKAEMLEIVQaiyKMVSSVMKMPEDESTpekrTEKIFRQMDTNRDGKLSLEEFIR 171
Cdd:cd00213  21 EGDKDtLSKKELKELLE---TELPNFLKNQKDPEA----VDKIMKDLDVNKDGKVDFQEFLV 75

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.

Pssm-ID: 320013 Cd Length: 104 Bit Score: 38.80 E-value: 2.34e-04

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 98985785  98 EQKLKWAFSMYDLDGNGYISKAEmleiVQAIYKMVSSVMKmpedestPEKRTEKIFRQMDTNRDGKLSLEEF 169
Cdd:cd16234  38 EQVLDWKFSQLDKNKNGVLERKE----WKPFKRLLKKAVK-------PKKCARKFPKYCDVNKDKKISLTEW 98

EF-hand motif found in eukaryotic phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11) isozymes; PI-PLC isozymes are signaling enzymes that hydrolyze the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. This family corresponds to the four EF-hand motifs containing PI-PLC isozymes, including PI-PLC-beta (1-4), -gamma (1-2), -delta (1,3,4), -epsilon (1), -zeta (1), eta (1-2). Lower eukaryotes such as yeast and slime molds contain only delta-type isozymes. In contrast, other types of isoforms present in higher eukaryotes. This family also includes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase 1 (PLC1) from fungi. Some homologs from plants contain only two atypical EF-hand motifs and they are not included. All PI-PLC isozymes except sperm-specific PI-PLC-zeta share a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C2 domain. PI-PLC-zeta lacks the PH domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Most of EF-hand motifs found in PI-PLCs consist of a helix-loop-helix structure, but lack residues critical to metal binding. Moreover, the EF-hand region of most of PI-PLCs may have an important regulatory function, but it has yet to be identified. However, PI-PLC-zeta is a key exception. It is responsible for Ca2+ oscillations in fertilized oocytes and exhibits a high sensitivity to Ca2+ mediated through its EF-hand domain. In addition, PI-PLC-eta2 shows a canonical EF-loop directing Ca2+-sensitivity and thus can amplify transient Ca2+ signals. Also it appears that PI-PLC-delta1 can regulate the binding of PH domain to PIP2 in a Ca2+-dependent manner through its functionally important EF-hand domains. PI-PLCs can be activated by a variety of extracellular ligands, such as growth factors, hormones, cytokines and lipids. Their activation has been implicated in tumorigenesis and/or metastasis linked to migration, proliferation, growth, inflammation, angiogenesis and actin cytoskeleton reorganization. PI-PLC-beta isozymes are activated by G-protein coupled receptor (GPCR) through different mechanisms. However, PI-PLC-gamma isozymes are activated by receptor tyrosine kinase (RTK), such as Rho and Ras GTPases. In contrast, PI-PLC-epsilon are activated by both GPCR and RTK. PI-PLC-delta1 and PLC-eta 1 are activated by GPCR-mediated calcium mobilization. The activation mechanism for PI-PLC-zeta remains unclear.

Pssm-ID: 320029 [Multi-domain] Cd Length: 137 Bit Score: 39.19 E-value: 3.01e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  40 SGHLSMEEFKKIYGNFFPYGDaSKFAEHVFRTFDANGDGTIDFREFIIAL-SVTSRGKLEQklkwAFSMYDLDGNGYISK 118
Cdd:cd15898  14 DGKLSLKEIKKLLKRLNIRVS-EKELKKLFKEVDTNGDGTLTFDEFEELYkSLTERPELEP----IFKKYAGTNRDYMTL 88

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....
gi 98985785 119 AEMLEIVQAIykmvssvmkmpEDESTPEKRTEKIFRQMDTNRDGK-LSLEEFIR 171
Cdd:cd15898  89 EEFIRFLREE-----------QGENVSEEECEELIEKYEPERENRqLSFEGFTN 131

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.

Pssm-ID: 320023 [Multi-domain] Cd Length: 278 Bit Score: 39.98 E-value: 3.75e-04

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 98985785  96 KLEQKLKWAFSMYDLDGNGYISKAEMLE-IVQaiykmvssvmKMPEDESTPEKRTEKIFRQMDTNRDGKLSLEEF 169
Cdd:cd16225  31 KKRKKLKEIFKKVDVNTDGFLSAEELEDwIME----------KTQEHFQEAVEENEQIFKAVDTDKDGNVSWEEY 95

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.

Pssm-ID: 425435 [Multi-domain] Cd Length: 29 Bit Score: 36.22 E-value: 4.94e-04

                          10        20
                  ....*....|....*....|....*....
gi 98985785   100 KLKWAFSMYDLDGNGYISKAEMLEIVQAI 128
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKKL 29

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.

Pssm-ID: 320080 [Multi-domain] Cd Length: 152 Bit Score: 38.36 E-value: 6.41e-04

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 98985785 104 AFSMYDLDGNGYISKAEMLEIVQAIYKMVSSVMKmpedeSTPEKRTEKIFRQMDT---------NRDGKLSLEEFIR 171
Cdd:cd15900   5 AFKMFDLDGDGELDKEEFNKVQSIIRSQTSVGQR-----HRDHTNGESTKLGMNStlaryffgkDGKQKLSIEKFLE 76

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.

Pssm-ID: 320075 [Multi-domain] Cd Length: 254 Bit Score: 39.26 E-value: 6.86e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785 105 FSMYDLDGNGYISKAEMLEIVQAIYKmvSSVMKMPEDESTPEKRTEkIFRQMDTNRDGKLSLEEFIRGAKSDPSIVRLLQ 184
Cdd:cd15902   5 WMHFDADGNGYIEGKELDSFLRELLK--ALNGKDKTDDEVAEKKKE-FMEKYDENEDGKIEIRELANILPTEENFLLLFR 81


                ....
gi 98985785 185 CDPS 188
Cdd:cd15902  82 REQP 85

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.

Pssm-ID: 320024 [Multi-domain] Cd Length: 264 Bit Score: 39.10 E-value: 6.94e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  73 DANGDGTIDFREFIIALsVTSRGKLEQkLKW------AFSMY-DLDGNGYISKAEMLEIVqaiykmvssvmkMPEDESTP 145
Cdd:cd16226 166 DKNKDGFISLEEYIGDM-YRDDDEEED-PDWvksereQFKEFrDKNKDGKMDREEVKDWI------------LPEDYDHA 231

                        90       100
                ....*....|....*....|...
gi 98985785 146 EKRTEKIFRQMDTNRDGKLSLEE 168
Cdd:cd16226 232 EAEAKHLIYEADDDKDGKLTKEE 254

EF hand;

Pssm-ID: 433035 [Multi-domain] Cd Length: 25 Bit Score: 35.37 E-value: 9.75e-04

                          10        20
                  ....*....|....*....|..
gi 98985785   150 EKIFRQMDTNRDGKLSLEEFIR 171
Cdd:pfam13202   2 KDTFRQIDLNGDGKISKEELRR 23

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.

Pssm-ID: 320021 [Multi-domain] Cd Length: 267 Bit Score: 38.96 E-value: 9.87e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  65 AEHVFRTFDANGDGTIDFREFIIAL----------------SVTSRGKLEQKLKWAFSMYDLDGNGYISKAEMLeivqai 128
Cdd:cd15899  73 SKEQFRAVDPDEDGHVSWDEYKNDTygsvgddeenvadnikEDEEYKKLLLKDKKRFEAADQDGDLILTLEEFL------ 146

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 98985785 129 ykmvssVMKMPED-ESTPEKRTEKIFRQMDTNRDGKLSLEEFIRGAKSDP 177
Cdd:cd15899 147 ------AFLHPEEsPYMLDFVIKETLEDLDKNGDGFISLEEFISDPYSAD 190

Calgranulins: S-100 domain found in proteins belonging to the Calgranulin subgroup of the S100 family of EF-hand calcium-modulated proteins, including S100A8, S100A9, and S100A12 . Note that the S-100 hierarchy, to which this Calgranulin group belongs, contains only S-100 EF-hand domains, other EF-hands have been modeled separately. These proteins are expressed mainly in granulocytes, and are involved in inflammation, allergy, and neuritogenesis, as well as in host-parasite response. Calgranulins are modulated not only by calcium, but also by other metals such as zinc and copper. Structural data suggested that calgranulins may exist in multiple structural forms, homodimers, as well as hetero-oligomers. For example, the S100A8/S100A9 complex called calprotectin plays important roles in the regulation of inflammatory processes, wound repair, and regulating zinc-dependent enzymes as well as microbial growth.

Pssm-ID: 240156 [Multi-domain] Cd Length: 88 Bit Score: 36.94 E-value: 1.01e-03

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 98985785  43 LSMEEFKKIY----GNFFPYGDASKFAEHVFRTFDANGDGTIDFREFII 87
Cdd:cd05030  27 LYKKEFKQLVekelPNFLKKEKNQKAIDKIFEDLDTNQDGQLSFEEFLV 75

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.

Pssm-ID: 320077 [Multi-domain] Cd Length: 248 Bit Score: 38.70 E-value: 1.08e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  40 SGHLSMEEFKKIYGNFF-----PYGDAS--KFAEHVFRTFDANGDGTIDFREFIIALSVTSRGKLE-QKLKWA------- 104
Cdd:cd16177 104 SGYIEANELKGFLSDLLkkanrPYDEKKlqEYTQTILRMFDLNGDGKLGLSEMARLLPVQENFLLKfQGMKLSseefnai 183

                        90       100
                ....*....|....*....|....*.
gi 98985785 105 FSMYDLDGNGYISKAEMLEIVQAIYK 130
Cdd:cd16177 184 FAFYDKDGSGYIDENELDALLKDLYE 209

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.

Pssm-ID: 320077 [Multi-domain] Cd Length: 248 Bit Score: 38.70 E-value: 1.09e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  63 KFAEHV---FRTFDANGDGTIDFREFIIALSVTSRGKL--------EQKLKWAFSMYDLDGNGYISKAEMLEIVQAIYKM 131
Cdd:cd16177  43 NFGEKMkefMQKYDKNADGRIEMAELAQILPTEENFLLcfrqhvgsSSEFMEAWRKYDTDRSGYIEANELKGFLSDLLKK 122

                        90       100       110       120
                ....*....|....*....|....*....|....*....|
gi 98985785 132 VSSvmkmPEDESTPEKRTEKIFRQMDTNRDGKLSLEEFIR 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.

Pssm-ID: 197492 [Multi-domain] Cd Length: 29 Bit Score: 35.05 E-value: 1.41e-03

                           10        20
                   ....*....|....*....|...
gi 98985785     68 VFRTFDANGDGTIDFREFIIALS 90
Cdd:smart00054   5 AFRLFDKDGDGKIDFEEFKDLLK 27

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).

Pssm-ID: 320025 [Multi-domain] Cd Length: 263 Bit Score: 38.07 E-value: 1.61e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  69 FRTFDANGDGTIDFREFI----------IALSVTSRGKLEQKL----KWAFSMYDLDGNGYISKAEMLEIVQaiykmvss 134
Cdd:cd16227  78 FEEADEDGDGKVTWEEYLadsfgyddedNEEMIKDSTEDDLKLleddKEMFEAADLNKDGKLDKTEFSAFQH-------- 149

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 98985785 135 vmkmPED-ESTPEKRTEKIFRQMDTNRDGKLSLEEFIRGAKSD 176
Cdd:cd16227 150 ----PEEyPHMHPVLIEQTLRDKDKDNDGFISFQEFLGDRAGH 188

EF-hand motif found in eukaryotic phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11) isozymes; PI-PLC isozymes are signaling enzymes that hydrolyze the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. This family corresponds to the four EF-hand motifs containing PI-PLC isozymes, including PI-PLC-beta (1-4), -gamma (1-2), -delta (1,3,4), -epsilon (1), -zeta (1), eta (1-2). Lower eukaryotes such as yeast and slime molds contain only delta-type isozymes. In contrast, other types of isoforms present in higher eukaryotes. This family also includes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase 1 (PLC1) from fungi. Some homologs from plants contain only two atypical EF-hand motifs and they are not included. All PI-PLC isozymes except sperm-specific PI-PLC-zeta share a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C2 domain. PI-PLC-zeta lacks the PH domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Most of EF-hand motifs found in PI-PLCs consist of a helix-loop-helix structure, but lack residues critical to metal binding. Moreover, the EF-hand region of most of PI-PLCs may have an important regulatory function, but it has yet to be identified. However, PI-PLC-zeta is a key exception. It is responsible for Ca2+ oscillations in fertilized oocytes and exhibits a high sensitivity to Ca2+ mediated through its EF-hand domain. In addition, PI-PLC-eta2 shows a canonical EF-loop directing Ca2+-sensitivity and thus can amplify transient Ca2+ signals. Also it appears that PI-PLC-delta1 can regulate the binding of PH domain to PIP2 in a Ca2+-dependent manner through its functionally important EF-hand domains. PI-PLCs can be activated by a variety of extracellular ligands, such as growth factors, hormones, cytokines and lipids. Their activation has been implicated in tumorigenesis and/or metastasis linked to migration, proliferation, growth, inflammation, angiogenesis and actin cytoskeleton reorganization. PI-PLC-beta isozymes are activated by G-protein coupled receptor (GPCR) through different mechanisms. However, PI-PLC-gamma isozymes are activated by receptor tyrosine kinase (RTK), such as Rho and Ras GTPases. In contrast, PI-PLC-epsilon are activated by both GPCR and RTK. PI-PLC-delta1 and PLC-eta 1 are activated by GPCR-mediated calcium mobilization. The activation mechanism for PI-PLC-zeta remains unclear.

Pssm-ID: 320029 [Multi-domain] Cd Length: 137 Bit Score: 37.26 E-value: 1.65e-03

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 98985785 100 KLKWAFSMYDLDGNGYISKAEMLEIVQAIykmvssvmkmpeDESTPEKRTEKIFRQMDTNRDGKLSLEEFIR 171
Cdd:cd15898   1 WLRRQWIKADKDGDGKLSLKEIKKLLKRL------------NIRVSEKELKKLFKEVDTNGDGTLTFDEFEE 60

EF-hand domain;

Pssm-ID: 463869 [Multi-domain] Cd Length: 30 Bit Score: 34.84 E-value: 1.76e-03

                          10        20
                  ....*....|....*....|....*....
gi 98985785   100 KLKWAFSMYDLDGNGYISKAEMLEIVQAI 128
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSL 29

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.

Pssm-ID: 320024 [Multi-domain] Cd Length: 264 Bit Score: 37.95 E-value: 2.07e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  68 VFRTFDANGDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDLDGNGYISKAEMLEIVQAIYKMVSSVMKMPEDESTPEK 147
Cdd:cd16226  40 IVDKIDKNGDGFVTEEELKDWIKYVQKKYIREDVDRQWKEYDPNKDGKLSWEEYKKATYGFLDDEEEDDDLHESYKKMIR 119

                        90       100
                ....*....|....*....|..
gi 98985785 148 RTEKIFRQMDTNRDGKLSLEEF 169
Cdd:cd16226 120 RDERRWKAADQDGDGKLTKEEF 141

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.

Pssm-ID: 320075 [Multi-domain] Cd Length: 254 Bit Score: 37.72 E-value: 2.31e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  68 VFRTFDANGDGTID-------FREFIIAL--SVTSRGKLEQKLKWAFSMYDLDGNGYISKAEMLEIV----------QAI 128
Cdd:cd15902   4 VWMHFDADGNGYIEgkeldsfLRELLKALngKDKTDDEVAEKKKEFMEKYDENEDGKIEIRELANILpteenflllfRRE 83

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
gi 98985785 129 YKMVSSVMKMpedestpekrteKIFRQMDTNRDGKLSLEEF 169
Cdd:cd15902  84 QPLISSVEFM------------KIWRKYDTDGSGFIEAKEL 112

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.

Pssm-ID: 425435 [Multi-domain] Cd Length: 29 Bit Score: 33.91 E-value: 2.73e-03

                          10        20
                  ....*....|....*....|....*.
gi 98985785   150 EKIFRQMDTNRDGKLSLEEFIRGAKS 175
Cdd:pfam00036   3 KEIFRLFDKDGDGKIDFEEFKELLKK 28

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.

Pssm-ID: 197492 [Multi-domain] Cd Length: 29 Bit Score: 33.89 E-value: 2.89e-03

                           10        20
                   ....*....|....*....|....*.
gi 98985785    150 EKIFRQMDTNRDGKLSLEEFIRGAKS 175
Cdd:smart00054   3 KEAFRLFDKDGDGKIDFEEFKDLLKA 28

EF-hand domain pair;

Pssm-ID: 463900 [Multi-domain] Cd Length: 67 Bit Score: 34.92 E-value: 3.09e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 98985785    40 SGHLSMEEFKKIYGNFFPYGDASK-FAEHVFRTFDANGDGTIDFREFIIALS 90
Cdd:pfam13499  16 DGYLDVEELKKLLRKLEEGEPLSDeEVEELFKEFDLDKDGRISFEEFLELYS 67

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.

Pssm-ID: 320058 [Multi-domain] Cd Length: 165 Bit Score: 36.85 E-value: 3.15e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|
gi 98985785  72 FDANGDGTIDFREFiialsvTSRGKLEQKLKWAFSMYDLDGNGYISKAEM 121
Cdd:cd16183  46 FDRDNSGTINFQEF------AALWKYITDWQNCFRSFDRDNSGNIDKNEL 89

EF-hand domain pair;

Pssm-ID: 404678 [Multi-domain] Cd Length: 54 Bit Score: 34.60 E-value: 3.23e-03

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 98985785    39 PSGHLSMEEFKKIYgNFFPYGDASKF-AEHVFRTFDANGDGTIDFREFIIAL 89
Cdd:pfam13833   1 EKGVITREELKRAL-ALLGLKDLSEDeVDILFREFDTDGDGYISFDEFCVLL 51

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+.

Pssm-ID: 320055 [Multi-domain] Cd Length: 164 Bit Score: 36.74 E-value: 3.31e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  25 HEIQEWYKGFLR---DcPSGHLSMEEFKK-IYGnfFPYGDASKFAEHVFRTFDANGDGTIDFREFI-IALSVtsrgkleQ 99
Cdd:cd16180  64 KYIQDWRRLFRRfdrD-RSGSIDFNELQNaLSS--FGYRLSPQFVQLLVRKFDRRRRGSISFDDFVeACVTL-------K 133

                        90
                ....*....|....*..
gi 98985785 100 KLKWAFSMYDLDGNGYI 116
Cdd:cd16180 134 RLTDAFRKYDTNRTGYA 150

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.

Pssm-ID: 425435 [Multi-domain] Cd Length: 29 Bit Score: 33.91 E-value: 3.65e-03

                          10        20
                  ....*....|....*....|...
gi 98985785    68 VFRTFDANGDGTIDFREFIIALS 90
Cdd:pfam00036   5 IFRLFDKDGDGKIDFEEFKELLK 27

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.

Pssm-ID: 320076 [Multi-domain] Cd Length: 243 Bit Score: 36.74 E-value: 4.05e-03

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 98985785 104 AFSMYDLDGNGYISKAEMLEIVQAIYKMVssvmKMPEDESTPEKRTEKIFRQMDTNRDGKLSLEEFIR 171
Cdd:cd16176  90 TWRKYDADHSGFIEADELKSFLKDLLKKA----NKPFDESKLEEYTHTMLKMFDSNNDGKLGLTEMAR 153

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).

Pssm-ID: 320022 [Multi-domain] Cd Length: 268 Bit Score: 37.03 E-value: 4.32e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  62 SKFA-EHVFRTFDANGDGTIDFREFIIALSVTSRGK------LEQKLKWAfSMYDLDGNGYISKAEMLEIVqaiykmvss 134
Cdd:cd16224 159 TEFViQEALEEHDKDGDGFISLEEFLGDYRKDPTANedpewiIVEKDRFV-NDYDKDNDGKLDPQELLPWV--------- 228

                        90       100       110
                ....*....|....*....|....*....|....
gi 98985785 135 vmkMPEDESTPEKRTEKIFRQMDTNRDGKLSLEE 168
Cdd:cd16224 229 ---VPNNYGIAQEEALHLIDEMDLNGDGRLSEEE 259

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.

Pssm-ID: 238131 [Multi-domain] Cd Length: 88 Bit Score: 34.77 E-value: 4.52e-03

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 98985785  36 RDCPSGHLSMEEFKKI----YGNFFPYGDASKFAEHVFRTFDANGDGTIDFREFIIAL 89
Cdd:cd00213  20 KEGDKDTLSKKELKELleteLPNFLKNQKDPEAVDKIMKDLDVNKDGKVDFQEFLVLI 77

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.

Pssm-ID: 320079 [Multi-domain] Cd Length: 261 Bit Score: 36.62 E-value: 4.66e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  60 DASKFAEHVFRTFDANGDGTIDFRE----------FIIALSVTSrgKLEQKLKW--AFSMYDLDGNGYISKAEMLEIVQA 127
Cdd:cd16179  46 ALEELKEEFMEAYDENQDGRIDIRElaqllpteenFLLLFRRDN--PLDSSVEFmkVWREYDKDNSGYIEADELKNFLKH 123

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 98985785 128 IYKMvssvmKMPEDESTPEK---RTEKIFRQMDTNRDGKLSLEEFIR 171
Cdd:cd16179 124 LLKE-----AKRDNDVSEDKlieYTDTILQLFDRNKDGKLQLSEMAR 165

Calgranulins: S-100 domain found in proteins belonging to the Calgranulin subgroup of the S100 family of EF-hand calcium-modulated proteins, including S100A8, S100A9, and S100A12 . Note that the S-100 hierarchy, to which this Calgranulin group belongs, contains only S-100 EF-hand domains, other EF-hands have been modeled separately. These proteins are expressed mainly in granulocytes, and are involved in inflammation, allergy, and neuritogenesis, as well as in host-parasite response. Calgranulins are modulated not only by calcium, but also by other metals such as zinc and copper. Structural data suggested that calgranulins may exist in multiple structural forms, homodimers, as well as hetero-oligomers. For example, the S100A8/S100A9 complex called calprotectin plays important roles in the regulation of inflammatory processes, wound repair, and regulating zinc-dependent enzymes as well as microbial growth.

Pssm-ID: 240156 [Multi-domain] Cd Length: 88 Bit Score: 34.63 E-value: 5.46e-03

                        10        20
                ....*....|....*....|....*
gi 98985785 146 EKRTEKIFRQMDTNRDGKLSLEEFI 170
Cdd:cd05030  50 QKAIDKIFEDLDTNQDGQLSFEEFL 74

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.

Pssm-ID: 320076 [Multi-domain] Cd Length: 243 Bit Score: 36.35 E-value: 6.10e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  40 SGHLSMEEFKKIYGNFF-----PYgDASKFAEH---VFRTFDANGDGTIDFREFIIALSVTSRGKLE-QKLKW------- 103
Cdd:cd16176  99 SGFIEADELKSFLKDLLkkankPF-DESKLEEYthtMLKMFDSNNDGKLGLTEMARLLPVQENFLLKfQGVKMcgkefnk 177

                        90
                ....*....|....*...
gi 98985785 104 AFSMYDLDGNGYISKAEM 121
Cdd:cd16176 178 IFELYDQDGNGYIDENEL 195

EF hand;

Pssm-ID: 433035 [Multi-domain] Cd Length: 25 Bit Score: 33.06 E-value: 6.36e-03

                          10        20
                  ....*....|....*....|
gi 98985785    66 EHVFRTFDANGDGTIDFREF 85
Cdd:pfam13202   2 KDTFRQIDLNGDGKISKEEL 21

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).

Pssm-ID: 319995 [Multi-domain] Cd Length: 106 Bit Score: 34.81 E-value: 6.92e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  91 VTSRGKLEQKLKWAFSMYDLDGNGYISKAEMLEIVQAIykmVSSVMKMP-EDEstpekRTEKIFRQMDTNRDGKLSLEEF 169
Cdd:cd16252  29 FQTSEQQEEAIRKAFQMLDKDKSGFIEWNEIKYILSTV---PSSMPVAPlSDE-----EAEAMIQAADTDGDGRIDFQEF 100

serine/threonine protein phosphatase 2A regulatory subunit B"; Heterotrimeric serine/threonine protein phosphatase 2A (PP2A) consists of scaffolding (A), catalytic (C), and variable (B, B', and B") subunits. The variable subunits dictate subcellular localization and substrate specificity of the PP2A holoenzyme. This family includes PP2A regulatory B'' subunits alpha, beta and gamma, encoded by PPP2R3A, PPP2R3B and PPP2R3C, respectively. It also includes subunit delta encoded by PPP2R3D in mouse. These B-family regulatory subunits play various roles including regulation of cytoskeletal assembly, neuronal differentiation, mitogen-activated protein kinase signaling, and apoptosis. Subunits alpha and beta contain two-domain elongated structure with two calcium EF-hands which mediate Ca2+-dependent changes in phosphatase activity.

Pssm-ID: 410336 Cd Length: 259 Bit Score: 36.02 E-value: 7.32e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785   8 LRPEVMQDLLESTDFTE-HEIQEWYkgflrdcpsghlSMEEFKKIYGNFFP----------------YGDA---SKFAEH 67
Cdd:cd21339  75 RASSFLQDLALLEEEEDiNQETNWF------------SYEHFYVIYCKFWEldtdhdlmiskedlsrYNDAamsNVFIDR 142

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985785  68 VF-----RTFDANGDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDLDGNGYISKAEMleivQAIYKMVSSVMKMPEDE 142
Cdd:cd21339 143 IFsgavtRGKTIQKEGEMSYADFVWFLISEEDKKEPTSIEYWFRCLDIDGDGYLSVFEL----EYFYEEQCERMKIHGIE 218

                       170       180       190
                ....*....|....*....|....*....|
gi 98985785 143 STP-EKRTEKIFRQMDTNRDGKLSLEEFIR 171
Cdd:cd21339 219 PLPfQDVLCQILDLVKPKDPGKITLQDLKR 248

EF-hand domain;

Pssm-ID: 463869 [Multi-domain] Cd Length: 30 Bit Score: 32.92 E-value: 7.80e-03

                          10        20
                  ....*....|....*....|....*.
gi 98985785   150 EKIFRQMDTNRDGKLSLEEFIRGAKS 175
Cdd:pfam13405   3 REAFKLFDKDGDGKISLEELRKALRS 28