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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720367415  38 SGVVNEETFKQIYAQFFphgdastyaHYLFNAFDTTQTGSVKFEDFVTALSILLRGTVHEKLRWTFNLYDINKDGYINKE 117
Cdd:COG5126    19 DGVLERDDFEALFRRLW---------ATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISAD 89

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1720367415 118 EMMDIVKAIydmmgkytypvlkeDTPRQHVDVFFQKMDKNKDGIVTLDEFLESCQE 173
Cdd:COG5126    90 EFRRLLTAL--------------GVSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720367415  38 SGVVNEETFKQIYAQFFphgdastyaHYLFNAFDTTQTGSVKFEDFVTALSILLRGTVHEKLRWTFNLYDINKDGYINKE 117
Cdd:COG5126    19 DGVLERDDFEALFRRLW---------ATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISAD 89

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1720367415 118 EMMDIVKAIydmmgkytypvlkeDTPRQHVDVFFQKMDKNKDGIVTLDEFLESCQE 173
Cdd:COG5126    90 EFRRLLTAL--------------GVSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

EF-hand domain pair;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1720367415  97 EKLRWTFNLYDINKDGYINKEEMMDIVKAIYdmmgkytypvLKEDTPRQHVDVFFQKMDKNKDGIVTLDEFLE 169
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKLE----------EGEPLSDEEVEELFKEFDLDKDGRISFEEFLE 64

centrin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720367415  95 VHEKLRWTFNLYDINKDGYINKEEMMDIVKAiydmmgkytypvLKEDTPRQHVDVFFQKMDKNKDGIVTLDEFLESC--- 171
Cdd:PTZ00183   15 QKKEIREAFDLFDTDGSGTIDPKELKVAMRS------------LGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMtkk 82

                          90
                  ....*....|....*..
gi 1720367415 172 ----QEDDNIMRSLQLF 184
Cdd:PTZ00183   83 lgerDPREEILKAFRLF 99

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720367415  38 SGVVNEETFKQIYAQFFphgdastyaHYLFNAFDTTQTGSVKFEDFVTALSILLRGTVHEKLRWTFNLYDINKDGYINKE 117
Cdd:COG5126    19 DGVLERDDFEALFRRLW---------ATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISAD 89

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1720367415 118 EMMDIVKAIydmmgkytypvlkeDTPRQHVDVFFQKMDKNKDGIVTLDEFLESCQE 173
Cdd:COG5126    90 EFRRLLTAL--------------GVSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

EF-hand domain pair;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1720367415  97 EKLRWTFNLYDINKDGYINKEEMMDIVKAIYdmmgkytypvLKEDTPRQHVDVFFQKMDKNKDGIVTLDEFLE 169
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKLE----------EGEPLSDEEVEELFKEFDLDKDGRISFEEFLE 64

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1720367415  97 EKLRWTFNLYDINKDGYINKEEMMDIVkaiYDMMgkytypvlkedtPRQH-VDVFFQKMDKNKDGIVTLDEFLE 169
Cdd:cd00252    45 EIAQWEFDNLDNNKDGKLDKRELAPFR---APLM------------PLEHcARGFFESCDLNKDKKISLQEWLG 103

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 1720367415   98 KLRWTFNLYDINKDGYINKEEMMDIVKAI 126
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1720367415  66 LFNAFDTTQTGSVKFEDFVTALSILLRGTVHEKLRWTFNLYDiNKDGYINKE-------EMMDIVKAIY 127
Cdd:cd15901    59 LLNLYDRNRTGCIRLLSVKIALITLCAASLLDKYRYLFGQLA-DSSGFISRErltqflqDLLQIPDLIG 126

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 1720367415  98 KLRWTFNLYDINKDGYINKEEMMDIVKAI 126
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKKL 29

Penta-EF hand, calcium binding motifs, found in Group I PEF proteins; The family corresponds to Group I PEF proteins that have been found not only in higher animals but also in lower animals, plants, fungi and protists. Group I PEF proteins include apoptosis-linked gene 2 protein (ALG-2), peflin and similar proteins. ALG-2, also termed programmed cell death protein 6 (PDCD6), is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination. Peflin is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720367415  66 LFNAFDTTQTGSVKFEDFVtalsillrGTVHEKLRWT--FNLYDINKDGYINKEEMmdiVKAIYdMMGkytYPVlkedtP 143
Cdd:cd16180    42 MINMFDRDRSGTINFDEFV--------GLWKYIQDWRrlFRRFDRDRSGSIDFNEL---QNALS-SFG---YRL-----S 101

                          90       100
                  ....*....|....*....|....*...
gi 1720367415 144 RQHVDVFFQKMDKNKDGIVTLDEFLESC 171
Cdd:cd16180   102 PQFVQLLVRKFDRRRRGSISFDDFVEAC 129

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 1720367415  62 YAHYLFNAFDTTQTGSVKFEDFVTALSILlrgTVHEKLRWTFNLYDINKDGYINKEEMMDIVKAiydmmgkytypVLKED 141
Cdd:cd15898    37 ELKKLFKEVDTNGDGTLTFDEFEELYKSL---TERPELEPIFKKYAGTNRDYMTLEEFIRFLRE-----------EQGEN 102

                          90       100
                  ....*....|....*....|....*...
gi 1720367415 142 TPRQHVDVFFQKMDKN-KDGIVTLDEFL 168
Cdd:cd15898   103 VSEEECEELIEKYEPErENRQLSFEGFT 130

EF-hand, calcium binding motif, found in calumenin, reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins; The family corresponds to a group of six EF-hand Ca2+-binding proteins, including calumenin (also known as crocalbin or CBP-50), reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins. Calumenin is an endo/sarcoplasmic reticulum (ER/SR) resident low-affinity Ca2+-binding protein that contains six EF-hand domains and a C-terminal SR retention signal His-Asp-Glu-Phe (HDEF) tetrapeptide. It functions as a novel regulator of SERCA2, and its expressional changes are tightly coupled with Ca2+-cycling of cardiomyocytes. It is also broadly involved in haemostasis and in the pathophysiology of thrombosis. Moreover, the extracellular calumenin acts as a suppressor of cell migration and tumor metastasis. RCN-1 is an endoplasmic reticulum resident Ca2+-binding protein with a carboxyl-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide signal. It acts as a potential negative regulator of B-RAF activation and can negatively modulate cardiomyocyte hypertrophy by inhibition of the mitogen-activated protein kinase signalling cascade. It also plays a key role in the development of doxorubicin-associated resistance. RCN-3 is a putative six EF-hand Ca2+-binding protein that contains five RXXR (X is any amino acid) motifs and a C-terminal ER retrieval signal HDEL tetrapeptide. The RXXR motif represents the target sequence of subtilisin-like proprotein convertases (SPCs). RCN-3 is specifically bound to the paired basic amino-acid-cleaving enzyme-4 (PACE4) precursor protein and plays an important role in the biosynthesis of PACE4.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1720367415  96 HEKLRWtfNLYDINKDGYINKEEMMDIVkaiydmmgkytYPvlkEDTPRQH---VDVFFQKMDKNKDGIVTLDEFL 168
Cdd:cd16226   120 RDERRW--KAADQDGDGKLTKEEFTAFL-----------HP---EEFPHMRdivVQETLEDIDKNKDGFISLEEYI 179

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1720367415 101 WTFNLYDINKDGYINKEEMmDIVKAIYDMMGKYTYPvlkedtprqhvdvFFQKMDKNKDGIVTLDEFLE 169
Cdd:pfam10591  57 WMFKRLDTNDDLLLDHEEL-APIRAPLKPEEHCIKP-------------FFESCDANKDKLISLEEWCC 111

centrin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720367415  95 VHEKLRWTFNLYDINKDGYINKEEMMDIVKAiydmmgkytypvLKEDTPRQHVDVFFQKMDKNKDGIVTLDEFLESC--- 171
Cdd:PTZ00183   15 QKKEIREAFDLFDTDGSGTIDPKELKVAMRS------------LGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMtkk 82

                          90
                  ....*....|....*..
gi 1720367415 172 ----QEDDNIMRSLQLF 184
Cdd:PTZ00183   83 lgerDPREEILKAFRLF 99