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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4406348   37 DQVYNTFDTNKDGFVDFLEFIAAVNLIMQEKMEQKLKWYFKLYDADGNGSIDKNELldmFMAVQALNGqqtlsPEEFINL 116
Cdd:COG5126  36 ATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEF---RRLLTALGV-----SEEEADE 107

                        90
                ....*....|.
gi 4406348  117 VFHKIDINNDG 127
Cdd:COG5126 108 LFARLDTDGDG 118

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4406348   37 DQVYNTFDTNKDGFVDFLEFIAAVNLIMQEKMEQKLKWYFKLYDADGNGSIDKNELldmFMAVQALNGqqtlsPEEFINL 116
Cdd:COG5126  36 ATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEF---RRLLTALGV-----SEEEADE 107

                        90
                ....*....|.
gi 4406348  117 VFHKIDINNDG 127
Cdd:COG5126 108 LFARLDTDGDG 118

EF-hand domain pair;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4406348     69 EQKLKWYFKLYDADGNGSIDKNELLDMFmavQALNGQQTLSPEEfINLVFHKIDINNDGngatlyWITFPtkgiDFRRIY 148
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLL---RKLEEGEPLSDEE-VEELFKEFDLDKDG------RISFE----EFLELY 66

                  .
gi 4406348    149 Q 149
Cdd:pfam13499  67 S 67

Eps15 homology domain; Pair of EF hand motifs that recognise proteins containing Asn-Pro-Phe (NPF) sequences.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4406348      37 DQVYNTFDTNKDGFVDFLEfiaAVNLIMQEKMEQKL---KWyfKLYDADGNGSIDKNEL-LDMFMAVQALNGQQ---TLS 109
Cdd:smart00027  13 EQIFRSLDKNQDGTVTGAQ---AKPILLKSGLPQTLlakIW--NLADIDNDGELDKDEFaLAMHLIYRKLNGYPipaSLP 87

                   ..
gi 4406348     110 PE 111
Cdd:smart00027  88 PS 89

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 4406348     10 PSGLQTLHEFKTLLGLQGLNQKANKHIDQVYNTFDTNKDGFVDFLEFIAAV 60
Cdd:pfam13833   1 EKGVITREELKRALALLGLKDLSEDEVDILFREFDTDGDGYISFDEFCVLL 51

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4406348   37 DQVYNTFDTNKDGFVDFLEFIAAVNLIMQEKMEQKLKWYFKLYDADGNGSIDKNELldmFMAVQALNGqqtlsPEEFINL 116
Cdd:COG5126  36 ATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEF---RRLLTALGV-----SEEEADE 107

                        90
                ....*....|.
gi 4406348  117 VFHKIDINNDG 127
Cdd:COG5126 108 LFARLDTDGDG 118

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 4406348   71 KLKWYFKLYDADGNGSIDKNELldmFMAVQALNGQQTlspEEFINLVFHKIDINNDG 127
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADEL---KAALKSLGEGLS---EEEIDEMIREVDKDGDG 51

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4406348   66 EKMEQKLKWYFKLYDADGNGSIDKNELLDMFMAVQAL-------NGQQTLSPEEFINLV---------------FHKIDI 123
Cdd:COG5126   1 DLQRRKLDRRFDLLDADGDGVLERDDFEALFRRLWATlfseadtDGDGRISREEFVAGMeslfeatvepfaraaFDLLDT 80

                ....
gi 4406348  124 NNDG 127
Cdd:COG5126  81 DGDG 84

centrin; Provisional

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 4406348    27 GLNQKANKHIDQVYNTFDTNKDGFVDFLEFIAAVNLIMQEKMEQKLKWYFKLYDADGNGSIDKNELLDM 95
Cdd:PTZ00183  10 GLTEDQKKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDI 78

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 4406348   36 IDQVYNTFDTNKDGFVDFLEFIAavnlimQEKMEQKLKWYF-------KLYDADGNGSIDKNELL 93
Cdd:cd16227 161 IEQTLRDKDKDNDGFISFQEFLG------DRAGHEDKEWLLvekdrfdEDYDKDGDGKLDGEEIL 219

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 4406348   11 SGLQTLHEFKTLLGLQGLNQKaNKHIDQVYNTFDTNKDGFVDFLEFIAAV 60
Cdd:cd00051  14 DGTISADELKAALKSLGEGLS-EEEIDEMIREVDKDGDGKIDFEEFLELM 62

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 4406348   41 NTFDTNKDGFVDFLEFIAAVNLIMQekmeqklkW--YFKLYDADGNGSIDKNELldmfmaVQALNG-QQTLSPeEFINLV 117
Cdd:cd16180  44 NMFDRDRSGTINFDEFVGLWKYIQD--------WrrLFRRFDRDRSGSIDFNEL------QNALSSfGYRLSP-QFVQLL 108

                        90
                ....*....|
gi 4406348  118 FHKIDINNDG 127
Cdd:cd16180 109 VRKFDRRRRG 118

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 4406348     38 QVYNTFDTNKDGFVDFLEFIAAV-NLIMQEKM-EQKLKWYFKLYDADGNGSIDKNELLDMFM 97
Cdd:pfam13499   6 EAFKLLDSDGDGYLDVEELKKLLrKLEEGEPLsDEEVEELFKEFDLDKDGRISFEEFLELYS 67

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 4406348   44 DTNKDGFVDFLEFIAavNLIMQEKMEQKLKW-------YFKLYDADGNGSIDKNELL---------------DMFMAVQA 101
Cdd:cd15899 170 DKNGDGFISLEEFIS--DPYSADENEEEPEWvkvekerFVELRDKDKDGKLDGEELLswvdpsnqeialeeaKHLIAESD 247

                        90
                ....*....|....
gi 4406348  102 LNGQQTLSPEEFIN 115
Cdd:cd15899 248 ENKDGKLSPEEILD 261

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 4406348   11 SGLQTLHEFKTLLglQGLNQKANKHIDQV---------YNTFDTNKDGFVDFLEFiaAVNLIMQE---------KMEQK- 71
Cdd:cd16176  99 SGFIEADELKSFL--KDLLKKANKPFDESkleeythtmLKMFDSNNDGKLGLTEM--ARLLPVQEnfllkfqgvKMCGKe 174

                        90       100
                ....*....|....*....|.
gi 4406348   72 LKWYFKLYDADGNGSIDKNEL 92
Cdd:cd16176 175 FNKIFELYDQDGNGYIDENEL 195

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 4406348     71 KLKWYFKLYDADGNGSIDKNELLDMFMAV 99
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKKL 29

EF-hand, calcium binding motif, found in reticulocalbin-2 (RCN2); RCN2, also termed calcium-binding protein ERC-55, or E6-binding protein (E6BP), or TCBP-49, is an endoplasmic reticulum resident low-affinity Ca2+-binding protein that has been implicated in immunity, redox homeostasis, cell cycle regulation and coagulation. It is associated with tumorigenesis, in particular with transformation of cells of the cervix induced by human papillomavirus (HPV), through binding to human papillomavirus (HPV) E6 oncogenic protein. It specifically interacts with vitamin D receptor among nuclear receptors. RCN2 contains an N-terminal signal sequence followed by six copies of the EF-hand Ca2+-binding motif, and a C-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide that is required for retention of RCN2 in the endoplasmic reticulum (ER).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4406348   36 IDQVYNTFDTNKDGFVDFLEFIA------AVNLIMQEKMEQKLKwYFKLYDADGNGSIDKNELLDMFMAvqalnGQQTLS 109
Cdd:cd16224 163 IQEALEEHDKDGDGFISLEEFLGdyrkdpTANEDPEWIIVEKDR-FVNDYDKDNDGKLDPQELLPWVVP-----NNYGIA 236

                        90
                ....*....|....*...
gi 4406348  110 PEEFINLVfHKIDINNDG 127
Cdd:cd16224 237 QEEALHLI-DEMDLNGDG 253

EF-hand, calcium binding motif, found in homologs of mammalian apoptosis-linked gene 2 protein (ALG-2); The family includes some homologs of mammalian apoptosis-linked gene 2 protein (ALG-2) mainly found in lower eukaryotes, such as a parasitic protist Leishmarua major and a cellular slime mold Dictyostelium discoideum. These homologs contains five EF-hand motifs. Due to the presence of unfavorable residues at the Ca2+-coordinating positions, their non-canonical EF4 and EF5 hands may not bind Ca2+. Two Dictyostelium PEF proteins are the prototypes of this family. They may bind to cytoskeletal proteins and/or signal-transducing proteins localized to detergent-resistant membranes named lipid rafts, and occur as monomers or weak homo- or heterodimers like ALG-2. They can serve as a mediator for Ca2+ signaling-related Dictyostehum programmed cell death (PCD).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4406348   43 FDTNKDGFVDFLEFiAAVN---LIMQEKmeqklkwyFKLYDADGNGSIDKNElldMFMAVQAlNGQQtLSPEEFiNLVFH 119
Cdd:cd16185  45 FDRDGNGTIDFEEF-AALHqflSNMQNG--------FEQRDTSRSGRLDANE---VHEALAA-SGFQ-LDPPAF-QALFR 109

                ...
gi 4406348  120 KID 122
Cdd:cd16185 110 KFD 112

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.

                        10        20        30
                ....*....|....*....|....*....|..
gi 4406348   29 NQKANKHIDQVYNTFDTNKDGFVDFLEFIAAV 60
Cdd:cd05030  46 KEKNQKAIDKIFEDLDTNQDGQLSFEEFLVLV 77

Penta-EF hand, calcium binding motifs, found in PEF calpain family; The PEF calpain family belongs to the second group of penta-EF hand (PEF) proteins. It includes classical (also called conventional or typical) calpain (referring to a calcium-dependent papain-like enzymes, EC 3.4.22.17) large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14) and two calpain small subunits (CAPNS1 and CAPNS2), which are largely confined to animals (metazoans). These PEF-containing are nonlysosomal intracellular calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates in response to calcium signalling. The classical mu- and m-calpains are heterodimers consisting of homologous but a distinct (large) L-subunit/chain (CAPN1 or CAPN2) and a common (small) S-subunit/chain (CAPNS1 or CAPNS2). These L-subunits (CAPN1 and CAPN2) and S-subunit CAPNS1 are ubiquitously found in all tissues. Other calpains likely consist of an isolated L-subunit/chain alone. Many of them, such as CAPNS2, CAPN3 (in skeletal muscle, or lens), CAPN8 (in stomach), CAPN9 (in digestive tracts), CAPN11 (in testis), CAPN12 (in follicles), are tissue-specific and have specific functions in distinct organs. The L-subunits of similar structure (called CALPA and B) also have been found in Drosophila melanogaster. The S-subunit seems to have a chaperone-like function for proper folding of the L-subunit. The catalytic L-subunits contain a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain. The S-subunits only have the PEF domain following an N-terminal Gly-rich hydrophobic domain. The calpains undergo a rearrangement of the protein backbone upon Ca2+-binding.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 4406348   38 QVYNTFDTNKDGFVDFLEFiaavnlimqEKMEQKLKWY---FKLYDADGNGSIDKNELLDMFMA 98
Cdd:cd16182  46 SLIALMDTNGSGRLDLEEF---------KTLWSDLKKWqaiFKKFDTDRSGTLSSYELRKALES 100

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

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 4406348   41 NTFDTNKDGFVDFLEFIAAVNLIMQEKMEQKLKWYFKLYdADGNGSIDKnELLDMFMA 98
Cdd:cd15901  61 NLYDRNRTGCIRLLSVKIALITLCAASLLDKYRYLFGQL-ADSSGFISR-ERLTQFLQ 116