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
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 6755983   65 AQHAFRTFDKNGDGTIDFREFICALSITSRGSFEQKLNWAFNMYDLDGDGKITRVEMLEII 125
Cdd:cd00051   2 LREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755983    63 KFAQHAFRTFDKNGDGTIDFREFICALSITSRGSFEQKLNWAFNMYDLDGDGKITRVEMLEiieaiykmvgtviMMKM-- 140
Cdd:NF041410  27 QFQKQLFAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAA-------------AAPPpp 93

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 6755983   141 -NEDGLTPEQRVDKIFSKMDKNKDDQITLDEFKEAAKSDPS 180
Cdd:NF041410  94 pPPDQAPSTELADDLLSALDTDGDGSISSDELSAGLTSAGS 134

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 6755983      66 QHAFRTFDKNGDGTIDFREFICALS 90
Cdd:smart00054   3 KEAFRLFDKDGDGKIDFEEFKDLLK 27

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
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 6755983   65 AQHAFRTFDKNGDGTIDFREFICALSITSRGSFEQKLNWAFNMYDLDGDGKITRVEMLEII 125
Cdd:cd00051   2 LREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755983   40 SGRLNLEEFQQLYVKFFPYGDAsKFAQHAFRTFDKNGDGTIDFREFicALSITSRGSFEQKLNWAFNMYDLDGDGKITRV 119
Cdd:COG5126  47 DGRISREEFVAGMESLFEATVE-PFARAAFDLLDTDGDGKISADEF--RRLLTALGVSEEEADELFARLDTDGDGKISFE 123

                        90
                ....*....|
gi 6755983  120 EMLEIIEAIY 129
Cdd:COG5126 124 EFVAAVRDYY 133

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755983    63 KFAQHAFRTFDKNGDGTIDFREFICALSITSRGSFEQKLNWAFNMYDLDGDGKITRVEMLEiieaiykmvgtviMMKM-- 140
Cdd:NF041410  27 QFQKQLFAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAA-------------AAPPpp 93

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 6755983   141 -NEDGLTPEQRVDKIFSKMDKNKDDQITLDEFKEAAKSDPS 180
Cdd:NF041410  94 pPPDQAPSTELADDLLSALDTDGDGSISSDELSAGLTSAGS 134

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755983   41 GRLNLEEFqqlyVKFF-PYGDASKFA---QHAFRTFDKNGDGTIDFREFIC-ALSITSRGSFEQKLNWAFNMYDLDGDGK 115
Cdd:cd16227 137 GKLDKTEF----SAFQhPEEYPHMHPvliEQTLRDKDKDNDGFISFQEFLGdRAGHEDKEWLLVEKDRFDEDYDKDGDGK 212

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 6755983  116 ITRVEMLeiieaiykmvgTVIMMKMNEdglTPEQRVDKIFSKMDKNKDDQITLDE 170
Cdd:cd16227 213 LDGEEIL-----------SWLVPDNEE---IAEEEVDHLFASADDDHDDRLSFDE 253

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755983    68 AFRTFDKNGDGTIDFREFICALSitSRGsFEQKLNWAFNMY---DLDGDGKITRVEMLEIIEAiykmvgtvimmKMNEDg 144
Cdd:PTZ00183  22 AFDLFDTDGSGTIDPKELKVAMR--SLG-FEPKKEEIKQMIadvDKDGSGKIDFEEFLDIMTK-----------KLGER- 86

                         90       100       110
                 ....*....|....*....|....*....|..
gi 6755983   145 lTPEQRVDKIFSKMDKNKDDQITLDEFKEAAK 176
Cdd:PTZ00183  87 -DPREEILKAFRLFDDDKTGKISLKNLKRVAK 117

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755983    73 DKNGDGTIDFREFICALSITSRGS-FEQKLNWAFNMYDLDGDGKITRVEMLEIieaiykmvgtviMMKMNEDgLTpEQRV 151
Cdd:PTZ00184  57 DADGNGTIDFPEFLTLMARKMKDTdSEEEIKEAFKVFDRDGNGFISAAELRHV------------MTNLGEK-LT-DEEV 122

                         90       100
                 ....*....|....*....|
gi 6755983   152 DKIFSKMDKNKDDQITLDEF 171
Cdd:PTZ00184 123 DEMIREADVDGDGQINYEEF 142

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 6755983   40 SGRLNLEEFQQLYVKFFPYGDASKFAQhAFRTFDKNGDGTIDFREFICAL-SITSRGSFEQklnwAFNMYDLDGDGKITR 118
Cdd:cd15898  14 DGKLSLKEIKKLLKRLNIRVSEKELKK-LFKEVDTNGDGTLTFDEFEELYkSLTERPELEP----IFKKYAGTNRDYMTL 88

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....
gi 6755983  119 VEMLEIIEAIYKMVgtvimmkmnedglTPEQRVDKIFSKMDKN-KDDQITLDEF 171
Cdd:cd15898  89 EEFIRFLREEQGEN-------------VSEEECEELIEKYEPErENRQLSFEGF 129

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 6755983      66 QHAFRTFDKNGDGTIDFREFICALS 90
Cdd:smart00054   3 KEAFRLFDKDGDGKIDFEEFKDLLK 27

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
                ....*....|....*....|....*....|....
gi 6755983  143 DGLTPEQ---RVDKIFSKMDKNKDDQITLDEFKE 173
Cdd:cd16226  26 DQLTPEEskeRLGIIVDKIDKNGDGFVTEEELKD 59

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 6755983     100 KLNWAFNMYDLDGDGKITRVEMLEIIEAI 128
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

transaldolase;

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 6755983   105 FNMYDLDGDGKITRVEMLeiieaiykmvGTvimmkmnedgltpeqrvDKIFSKMDKNKDDQITLDE 170
Cdd:PRK12309 340 FRLYDLDGDGFITREEWL----------GS-----------------DAVFDALDLNHDGKITPEE 378

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755983    73 DKNGDGTIDFREF--ICALSITSRGSFEQKLNwAFNMYDLDGDGKITRVEMleiieaiyKMVGTVIMMKMNEDGLtpeqr 150
Cdd:PTZ00183  63 DKDGSGKIDFEEFldIMTKKLGERDPREEILK-AFRLFDDDKTGKISLKNL--------KRVAKELGETITDEEL----- 128

                         90       100
                 ....*....|....*....|....*....
gi 6755983   151 vDKIFSKMDKNKDDQITLDEFKEAAKSDP 179
Cdd:PTZ00183 129 -QEMIDEADRNGDGEISEEEFYRIMKKTN 156

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 6755983     151 VDKIFSKMDKNKDDQITLDEFKEAAKS 177
Cdd:smart00054   2 LKEAFRLFDKDGDGKIDFEEFKDLLKA 28

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
                ....*....|....*....|....*....|....*....|..
gi 6755983   40 SGRLNLEEFQQLYVKFfpygdasKFAQHAFRTFDKNGDGTID 81
Cdd:cd16182  56 SGRLDLEEFKTLWSDL-------KKWQAIFKKFDTDRSGTLS 90

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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 6755983   28 KQWYKGFLKDcPSGRLNLEEFQQLYVKFfPYGDASKFAQHAFRTFDKNGDGTIDFREFI-CALSItsrgsfeQKLNWAFN 106
Cdd:cd16183  70 QNCFRSFDRD-NSGNIDKNELKQALTSF-GYRLSDQFYDILVRKFDRQGRGTIAFDDFIqCCVVL-------QTLTDSFR 140

                        90
                ....*....|.
gi 6755983  107 MYDLDGDGKIT 117
Cdd:cd16183 141 RYDTDQDGWIQ 151

Eps15 homology domain; found in proteins implicated in endocytosis, vesicle transport, and signal transduction. The alignment contains a pair of EF-hand motifs, typically one of them is canonical and binds to Ca2+, while the other may not bind to Ca2+. A hydrophobic binding pocket is formed by residues from both EF-hand motifs. The EH domain binds to proteins containing NPF (class I), [WF]W or SWG (class II), or H[TS]F (class III) sequence motifs.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 6755983  105 FNMYDLDGDGKITRVEMLEIieaiykmvgtviMMKMNedglTPEQRVDKIFSKMDKNKDDQITLDEF 171
Cdd:cd00052   5 FRSLDPDGDGLISGDEARPF------------LGKSG----LPRSVLAQIWDLADTDKDGKLDKEEF 55