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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22212900  66 LFNAFDTDHNGAVSFEDFIKGLSILLRGTVQEKLNWAFNLYDINKDGYITKEEMLDIMKAIydmmgkctypvlkeDAPRQ 145
Cdd:COG5126  38 LFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEFRRLLTAL--------------GVSEE 103

                        90       100
                ....*....|....*....|....*...
gi 22212900 146 HVETFFQKMDKNKDGVVTIDEFIESCQK 173
Cdd:COG5126 104 EADELFARLDTDGDGKISFEEFVAAVRD 131

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22212900  66 LFNAFDTDHNGAVSFEDFIKGLSILLRGTVQEKLNWAFNLYDINKDGYITKEEMLDIMKAIydmmgkctypvlkeDAPRQ 145
Cdd:COG5126  38 LFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEFRRLLTAL--------------GVSEE 103

                        90       100
                ....*....|....*....|....*...
gi 22212900 146 HVETFFQKMDKNKDGVVTIDEFIESCQK 173
Cdd:COG5126 104 EADELFARLDTDGDGKISFEEFVAAVRD 131

EF-hand domain pair;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 22212900    97 EKLNWAFNLYDINKDGYITKEEMLDIMKAIYdmmgkctypvLKEDAPRQHVETFFQKMDKNKDGVVTIDEFIE 169
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKLE----------EGEPLSDEEVEELFKEFDLDKDGRISFEEFLE 64

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22212900   44 ETFKEIYSQFFPQGDST-----------------TYAHF--LFNAFDTDHNGAVSFEDFIKGLSILLRGT-VQEKLNWAF 103
Cdd:PTZ00184  11 AEFKEAFSLFDKDGDGTittkelgtvmrslgqnpTEAELqdMINEVDADGNGTIDFPEFLTLMARKMKDTdSEEEIKEAF 90

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 22212900  104 NLYDINKDGYITKEEMLDIMKAiydmmgkctypvLKEDAPRQHVETFFQKMDKNKDGVVTIDEFI 168
Cdd:PTZ00184  91 KVFDRDGNGFISAAELRHVMTN------------LGEKLTDEEVDEMIREADVDGDGQINYEEFV 143

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22212900   66 LFNAFDTDHNGAVSFEDFIKGLSILLRGTVQEKLNWAFNLYDINKDGYITKEEMldimkaiyDMMGKCTYPVLKEDAPRQ 145
Cdd:NF041410  32 LFAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDEL--------AAAAPPPPPPPDQAPSTE 103

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 22212900  146 HVETFFQKMDKNKDGVVTIDEFIESCQKDENIMRSMQLF 184
Cdd:NF041410 104 LADDLLSALDTDGDGSISSDELSAGLTSAGSSADSSQLF 142

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22212900  66 LFNAFDTDHNGAVSFEDFIKGLSILLRGTVQEKLNWAFNLYDINKDGYITKEEMLDIMKAIydmmgkctypvlkeDAPRQ 145
Cdd:COG5126  38 LFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEFRRLLTAL--------------GVSEE 103

                        90       100
                ....*....|....*....|....*...
gi 22212900 146 HVETFFQKMDKNKDGVVTIDEFIESCQK 173
Cdd:COG5126 104 EADELFARLDTDGDGKISFEEFVAAVRD 131

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

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 22212900  98 KLNWAFNLYDINKDGYITKEEMLDIMKAIYDMMgkctypvlkedaPRQHVETFFQKMDKNKDGVVTIDEFIE 169
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLGEGL------------SEEEIDEMIREVDKDGDGKIDFEEFLE 60

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22212900  38 SGVVNEETFKEIYSQFFPQGDSTTyAHFLFNAFDTDHNGAVSFEDFIKGLSILlrGTVQEKLNWAFNLYDINKDGYITKE 117
Cdd:COG5126  47 DGRISREEFVAGMESLFEATVEPF-ARAAFDLLDTDGDGKISADEFRRLLTAL--GVSEEEADELFARLDTDGDGKISFE 123

                        90
                ....*....|
gi 22212900 118 EMLDIMKAIY 127
Cdd:COG5126 124 EFVAAVRDYY 133

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 22212900  64 HFLFNAFDTDHNGAVSFEDFIKglsilLRGTVQeklNW--AFNLYDINKDGYITKEEMLDIMKaiydMMGkctYPVlked 141
Cdd:cd16180  40 RLMINMFDRDRSGTINFDEFVG-----LWKYIQ---DWrrLFRRFDRDRSGSIDFNELQNALS----SFG---YRL---- 100

                        90       100       110
                ....*....|....*....|....*....|
gi 22212900 142 aPRQHVETFFQKMDKNKDGVVTIDEFIESC 171
Cdd:cd16180 101 -SPQFVQLLVRKFDRRRRGSISFDDFVEAC 129

Secreted protein acidic and rich in cysteine Ca binding region; The SPARC_Ca_bdg domain of Secreted Protein Acidic and Rich in Cysteine is responsible for the anti-spreading activity of human urothelial cells. It is rich in alpha-helices. This extracellular calcium-binding domain contains two EF-hands that each coordinates one Ca2+ ion, forming a helix-loop-helix structure that not only drives the conformation of the protein but is also necessary for biological activity. The anti-spreading activity was dependent on the coordination of Ca2+ by a Glu residue at the Z position of EF-hand 2.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22212900    68 NAFDTDHNGAVSFEDFIKGLSIllrgtVQEKLNWAFNLYDINKDGYITKEEmLDIMKAIYDMMGKCTYPvlkedaprqhv 147
Cdd:pfam10591  29 RRERKDHSSTLEKRDESLLYPC-----CKDPLGWMFKRLDTNDDLLLDHEE-LAPIRAPLKPEEHCIKP----------- 91

                          90       100
                  ....*....|....*....|
gi 22212900   148 etFFQKMDKNKDGVVTIDEF 167
Cdd:pfam10591  92 --FFESCDANKDKLISLEEW 109

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

                           10        20
                   ....*....|....*....|....*....
gi 22212900     98 KLNWAFNLYDINKDGYITKEEMLDIMKAI 126
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22212900  38 SGVVNEETFKEIYSQFFPQGdSTTYAHFLFNAFDTDHNGAVSFEDFIKGLSILlrgTVQEKLNWAFNLYDINKDGYITKE 117
Cdd:cd15898  14 DGKLSLKEIKKLLKRLNIRV-SEKELKKLFKEVDTNGDGTLTFDEFEELYKSL---TERPELEPIFKKYAGTNRDYMTLE 89

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 22212900 118 EMLDIMKAiydmmgkctypVLKEDAPRQHVETFFQKMDKN-KDGVVTIDEFI 168
Cdd:cd15898  90 EFIRFLRE-----------EQGENVSEEECEELIEKYEPErENRQLSFEGFT 130

EF-hand, calcium binding motif, found in reticulocalbin-2 (RCN2) mainly from protostomes; This family corresponds to a group of uncharacterized RCN2-like proteins, which are mainly found in protostomes. Although their biological function remains unclear, they show high sequence similarity with RCN2 (also known as E6BP or TCBP-49), which is an endoplasmic reticulum resident low-affinity Ca2+-binding protein that has been implicated in immunity, redox homeostasis, cell cycle regulation and coagulation. Members in this family contain six copies of the EF-hand Ca2+-binding motif, but may lack a C-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide that is required for retention of RCN2 in the endoplasmic reticulum (ER).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22212900  70 FDTDHNGAVSFEDFIKGLSILL--RGTVQEKLNWAfNLYDINKDGYITKEEMLDIMkaiydmmgkctYPVLKEDApRQHV 147
Cdd:cd16227 168 KDKDNDGFISFQEFLGDRAGHEdkEWLLVEKDRFD-EDYDKDGDGKLDGEEILSWL-----------VPDNEEIA-EEEV 234

                        90       100
                ....*....|....*....|..
gi 22212900 148 ETFFQKMDKNKDGVVTIDEFIE 169
Cdd:cd16227 235 DHLFASADDDHDDRLSFDEILD 256

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 22212900    98 KLNWAFNLYDINKDGYITKEEMLDIMKAI 126
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKKL 29

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 22212900  71 DTDHNGAVSFEDFIKglsiLLRGTV--QEKLNWAF-------NLYDINKDGYITKEEMLDIMkaiyDMMgkctypvlKED 141
Cdd:cd15899 170 DKNGDGFISLEEFIS----DPYSADenEEEPEWVKvekerfvELRDKDKDGKLDGEELLSWV----DPS--------NQE 233

                        90       100
                ....*....|....*....|....*...
gi 22212900 142 APRQHVETFFQKMDKNKDGVVTIDEFIE 169
Cdd:cd15899 234 IALEEAKHLIAESDENKDGKLSPEEILD 261

EF-hand domain;

                          10        20
                  ....*....|....*....|....*....
gi 22212900    98 KLNWAFNLYDINKDGYITKEEMLDIMKAI 126
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSL 29

EF-hand, calcium binding motif, found in 45 kDa calcium-binding protein (Cab45); Cab45, also termed stromal cell-derived factor 4 (SDF-4), is a soluble, lumenal Golgi resident low-affinity Ca2+-binding protein that contains six copies of the EF-hand Ca2+-binding motif. It is required for secretory pathway calcium ATPase1 (SPCA1)-dependent Ca2+ import into the trans-Golgi network (TGN) and plays an essential role in Ca2+-dependent secretory cargo sorting at the TGN.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 22212900 103 FNLYDINKDGYITKEEMLD-IMKAIYDMMgkctypvlkEDApRQHVETFFQKMDKNKDGVVTIDEF 167
Cdd:cd16225  40 FKKVDVNTDGFLSAEELEDwIMEKTQEHF---------QEA-VEENEQIFKAVDTDKDGNVSWEEY 95

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
                ....*....|....*....|....*....|....*....|....*....|.
gi 22212900  65 FLFNAFDTDHNGAVSFEDFIKGLSILLRgtvqekLNWAFNLYDINKDGYIT 115
Cdd:cd16180 107 LLVRKFDRRRRGSISFDDFVEACVTLKR------LTDAFRKYDTNRTGYAT 151

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

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 22212900  65 FLFNAFDTDHNGAVSFEDFIKGLSILLRGTVQEKLNWAFNLYDiNKDGYITKE-------EMLDIMKAIY 127
Cdd:cd15901  58 WLLNLYDRNRTGCIRLLSVKIALITLCAASLLDKYRYLFGQLA-DSSGFISRErltqflqDLLQIPDLIG 126

phosphatidylserine decarboxylase

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 22212900  107 DINKDGYITKEEMLDIMKAIYDMMGKctypvlkedaprQHVETFFQKMDKNKDGVVTIDE 166
Cdd:PLN02964 189 DYDEDGQLSFSEFSDLIKAFGNLVAA------------NKKEELFKAADLNGDGVVTIDE 236

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 22212900  25 LQILYRGFK--NECPSGVVN-EETFKEIYSQFFPQGDSTTYAhfLFNAFDTDHNGAVSFEDFIkGLSILLRGTvqeklNW 101
Cdd:cd16185  65 LSNMQNGFEqrDTSRSGRLDaNEVHEALAASGFQLDPPAFQA--LFRKFDPDRGGSLGFDDYI-ELCIFLASA-----RN 136

                        90
                ....*....|....
gi 22212900 102 AFNLYDINKDGYIT 115
Cdd:cd16185 137 LFQAFDRQRTGRVT 150