Mitochondrial carrier protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462567620 185 WWKQLVAGAVAGAVSRTGTAPLDRLKVFMQVHA--SKTNRLNILGGLRSMVLEGGIRSLWRGNGINVLKIAPESAIKFMA 262
Cdd:pfam00153   5 FLASLLAGGIAGAIAVTVTYPLDVVKTRLQVQGgsGKSKGRGILDCFKKIYKEEGIRGLYKGLLPNLLRVAPAAAIYFGT 84

                          90
                  ....*....|
gi 2462567620 263 YEQIKRAILG 272
Cdd:pfam00153  85 YETLKRLLLK 94

Mitochondrial carrier protein;

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 2462567620 317 DPGILVLLACGTISSTCGQIASYPLALVRTRMQAQG 352
Cdd:pfam00153   2 ELSFLASLLAGGIAGAIAVTVTYPLDVVKTRLQVQG 37

Mitochondrial carrier protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462567620 185 WWKQLVAGAVAGAVSRTGTAPLDRLKVFMQVHA--SKTNRLNILGGLRSMVLEGGIRSLWRGNGINVLKIAPESAIKFMA 262
Cdd:pfam00153   5 FLASLLAGGIAGAIAVTVTYPLDVVKTRLQVQGgsGKSKGRGILDCFKKIYKEEGIRGLYKGLLPNLLRVAPAAAIYFGT 84

                          90
                  ....*....|
gi 2462567620 263 YEQIKRAILG 272
Cdd:pfam00153  85 YETLKRLLLK 94

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 2462567620  85 MFHSLDRNQDGHIDVSEIQQSFRALGISISLEQAEKILHSMDRDGTMTIDWQEWRDHF 142
Cdd:cd00051     5 AFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2462567620  79 EQRLLLMFHSLDRNQDGHIDVSEIQQSFRALGISISL--EQAEKILHSMDRDGTMTIDWQE 137
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEPLsdEEVEELFKEFDLDKDGRISFEE 61

XopAW family type III secretion system calcium-binding effector;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462567620  16 RLFEELDSNKDGRVDVHELRQGLArlggGNPDPGAQQGIS---SEGDADPDGGLDLEEFSRYL------QEREQRLLL-- 84
Cdd:NF041410   31 QLFAKLDSDGDGSVSQDELSSALS----SKSDDGSLIDLSelfSDLDSDGDGSLSSDELAAAAppppppPDQAPSTELad 106

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2462567620  85 -MFHSLDRNQDGHIDVSEIQQSFRALGISISLEQAEKILHSmDRDGTMTID 134
Cdd:NF041410  107 dLLSALDTDGDGSISSDELSAGLTSAGSSADSSQLFSALDS-DGDGSVSSD 156

Mitochondrial carrier protein;

                          10        20        30
                  ....*....|....*....|....*....|
gi 2462567620 275 ETLHVQERFVAGSLAGATAQTIIYPMETLK 304
Cdd:pfam00153   1 SELSFLASLLAGGIAGAIAVTVTYPLDVVK 30

Mitochondrial carrier protein;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462567620 185 WWKQLVAGAVAGAVSRTGTAPLDRLKVFMQVHA--SKTNRLNILGGLRSMVLEGGIRSLWRGNGINVLKIAPESAIKFMA 262
Cdd:pfam00153   5 FLASLLAGGIAGAIAVTVTYPLDVVKTRLQVQGgsGKSKGRGILDCFKKIYKEEGIRGLYKGLLPNLLRVAPAAAIYFGT 84

                          90
                  ....*....|
gi 2462567620 263 YEQIKRAILG 272
Cdd:pfam00153  85 YETLKRLLLK 94

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462567620   8 AERRQRWGRLFEELDSNKDGRVDVHELRQGLARLGGGNPDPGAQQGISSeGDADPDGGLDLEEFSRYLQE---REQRLLL 84
Cdd:COG5126    29 ALFRRLWATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDL-LDTDGDGKISADEFRRLLTAlgvSEEEADE 107

                          90       100
                  ....*....|....*....|...
gi 2462567620  85 MFHSLDRNQDGHIDVSEIQQSFR 107
Cdd:COG5126   108 LFARLDTDGDGKISFEEFVAAVR 130

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 2462567620  12 QRWgrlFEELDSNKDGRVDVHELRQGLArlgGGNPDPG---AQQGISSEgDADPDGGLDLEEFS---RYLQEREQRlllm 85
Cdd:cd16185     3 RQW---FRAVDRDRSGSIDVNELQKALA---GGGLLFSlatAEKLIRMF-DRDGNGTIDFEEFAalhQFLSNMQNG---- 71

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2462567620  86 FHSLDRNQDGHIDVSEIQQSFRALGISISLEQAEKILHSMDRDGTMTIDWQEW 138
Cdd:cd16185    72 FEQRDTSRSGRLDANEVHEALAASGFQLDPPAFQALFRKFDPDRGGSLGFDDY 124

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 2462567620  16 RLFEELDSNKDGRVDVHELRQGLaRLGGGNPdpgaqqgISSEG--------DADPDGGLDLEEFS---RYLQeREQRLll 84
Cdd:cd16180     4 RIFQAVDRDRSGRISAKELQRAL-SNGDWTP-------FSIETvrlminmfDRDRSGTINFDEFVglwKYIQ-DWRRL-- 72

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 2462567620  85 mFHSLDRNQDGHIDVSEIQQSFRALGISISLEQAEKILHSMDRDGTMTI 133
Cdd:cd16180    73 -FRRFDRDRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSI 120

centrin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462567620  18 FEELDSNKDGRVDVHELRQGLARLGGGNPDPGAQQGISsEGDADPDGGLDLEEF----SRYLQEREQR--LLLMFHSLDR 91
Cdd:PTZ00183   23 FDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIA-DVDKDGSGKIDFEEFldimTKKLGERDPReeILKAFRLFDD 101

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 2462567620  92 NQDGHIDVSEIQQSFRALGISISLEQAEKILHSMDRDGTMTIDWQE 137
Cdd:PTZ00183  102 DKTGKISLKNLKRVAKELGETITDEELQEMIDEADRNGDGEISEEE 147

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2462567620  11 RQRWGRLFEELDSNKDGRVDVHELRQGLARLGGGNP-DPGAQQGISSEGDADPDGGLDLEEFSRYLQ 76
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEPlSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

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 2462567620  18 FEELDSNKDGRVDVHELRQGLARLGGGNPDPGAQQGIsSEGDADPDGGLDLEEFSRYLQ 76
Cdd:cd00051     6 FRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMI-REVDKDGDGKIDFEEFLELMA 63

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 2462567620  18 FEELDSNKDGRVDVHELRQGLARLGGGNPDPGAQQGISSE---------------GDADPDGGLDLEEFSRYLQEREQRL 82
Cdd:cd15899    77 FRAVDPDEDGHVSWDEYKNDTYGSVGDDEENVADNIKEDEeykklllkdkkrfeaADQDGDLILTLEEFLAFLHPEESPY 156

                          90       100
                  ....*....|....*....|....*
gi 2462567620  83 LLMF------HSLDRNQDGHIDVSE 101
Cdd:cd15899   157 MLDFviketlEDLDKNGDGFISLEE 181

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 2462567620  77 EREQRLLLMFHSLDRNQDGHIDVSE----IQQSFRALgisiSLEQAEKILHSMDRDGTMTIDWQE 137
Cdd:cd16227    33 EAKRRLAVLAKKMDLNDDGFIDRKElkawILRSFKML----DEEEANERFEEADEDGDGKVTWEE 93

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 2462567620  59 DADPDGGLDLEEFSRYLQER-----EQRLLLMFHSLDRNQDGHIDVSEIQQ 104
Cdd:cd00051    10 DKDGDGTISADELKAALKSLgeglsEEEIDEMIREVDKDGDGKIDFEEFLE 60

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).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462567620  64 GGLDLEEFSRYLQ------EREQRLLLMFHSLDRNQDGHIDVSEIQQSFRALGIS-----ISLEQAEKILHSMDRDGTMT 132
Cdd:cd16252    15 GSFNYSKFFEYMQkfqtseQQEEAIRKAFQMLDKDKSGFIEWNEIKYILSTVPSSmpvapLSDEEAEAMIQAADTDGDGR 94

                  ....*...
gi 2462567620 133 IDWQEWRD 140
Cdd:cd16252    95 IDFQEFSD 102

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
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 2462567620  82 LLLMFHSLDRNQDGHIDVSEIQQSFRALGISISLEQAEKILHSMDRDGTMTIDWQE 137
Cdd:cd16185     2 LRQWFRAVDRDRSGSIDVNELQKALAGGGLLFSLATAEKLIRMFDRDGNGTIDFEE 57

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 2462567620   8 AERRQRWGRLFEELDSNKDGRVDVHELR----QGLARLgggnpDPGAQQGISSEGDADPDG---------------GLDL 68
Cdd:cd16227    32 EEAKRRLAVLAKKMDLNDDGFIDRKELKawilRSFKML-----DEEEANERFEEADEDGDGkvtweeyladsfgydDEDN 106

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462567620  69 EEFSRYLQEREQRLL----LMFHSLDRNQDGHIDVSEiqqsFRA----------LGISIsleqaEKILHSMDRDGTMTID 134
Cdd:cd16227   107 EEMIKDSTEDDLKLLeddkEMFEAADLNKDGKLDKTE----FSAfqhpeeyphmHPVLI-----EQTLRDKDKDNDGFIS 177

                  ...
gi 2462567620 135 WQE 137
Cdd:cd16227   178 FQE 180

EF-hand motif found in phosphoinositide phospholipase C eta 1 (PI-PLC-eta1); PI-PLC-eta1, also termed 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1, or phospholipase C-eta-1 (PLC-eta-1), or phospholipase C-like protein 3 (PLC-L3), is a neuron-specific PI-PLC that is most abundant in the brain, particularly in the hippocampus, habenula, olfactory bulb, cerebellum, and throughout the cerebral cortex. It is also expressed in the zona incerta and in the spinal cord. PI-PLC-eta1 may perform a fundamental role in the brain. It may also act in synergy with other PLC subtypes. For instance, it is activated via intracellular Ca2+ mobilization and then plays a role in the amplification of GPCR (G-protein-coupled receptor)-mediated PLC-beta signals. In addition, its activity can be stimulated by ionomycin. PI-PLC-eta1 contains an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core domain, a C2 domain, and a unique C-terminal tail that terminates with a PDZ-binding motif, a potential interaction site for other signaling proteins. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. The C-terminal tail harbors a number of proline-rich motifs which may interact with SH3 (Src homology 3) domain-containing proteins, as well as many serine/threonine residues, suggesting possible regulation of interactions by protein kinases/phosphatases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462567620  18 FEELDSNKDGRVDVHELRQGLARLGGGNPDPGAQQgISSEGDADPD-GGLDLEEFSRYLQ----EREQRLLLMFHSLDRN 92
Cdd:cd16220     6 FEEADKNGDGLLNIEEIYQLMHKLNVNLPRRKVRQ-MFQEADTDENqGTLTFEEFCVFYKmmslRRDLYLLLLSYSDKKD 84

                          90
                  ....*....|....*
gi 2462567620  93 qdgHIDVSEIQQSFR 107
Cdd:cd16220    85 ---HLTVEELAQFLK 96

The penta-EF hand (PEF) family; The penta-EF hand (PEF) family contains a group of five EF-hand calcium-binding proteins, including several classical calpain large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14), two calpain small subunits (CAPNS1 and CAPNS2), as well as non-calpain PEF proteins, ALG-2 (apoptosis-linked gene 2, also termed programmed cell death protein 6, PDCD6), peflin, sorcin, and grancalcin. Based on the sequence similarity of EF1 hand, ALG-2 and peflin have been classified into group I PEF proteins. Calcium-dependent protease calpain subfamily members, sorcin and grancalcin, are group II PEF proteins. Calpains (EC 3.4.22.17) are calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates. They have been implicated in a number of physiological processes such as cell cycle progression, remodeling of cytoskeletal-cell membrane attachments, signal transduction, gene expression and apoptosis. ALG-2 is a pro-apoptotic factor that forms a homodimer in the cell or a heterodimer with its closest paralog peflin through their EF5s. Peflin is a 30-kD PEF protein with a longer N-terminal hydrophobic domain than any other member of the PEF family, and it contains nine nonapeptide (A/PPGGPYGGP) repeats. It exists only as a heterodimer with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. ALG-2 interacts with various proteins in a Ca2+-dependent manner. Sorcin (for soluble resistance-related calcium binding protein) is a soluble resistance-related calcium-binding protein that participates in the regulation of calcium homeostasis in cells. Grancalcin is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It plays a key role in leukocyte-specific functions that are responsible for host defense. Grancalcin can form a heterodimer together with sorcin. Members in this family contain five EF-hand motifs attached to an N-terminal region of variable length containing one or more short Gly/Pro-rich sequences. These proteins form homodimers or heterodimers through pairing between the 5th EF-hands from the two molecules. Unlike calmodulin, the PEF domains do not undergo major conformational changes upon binding Ca2+.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462567620  16 RLFEELDSnKDGRVDVHELRQGLARLGGGNPDPGAQ----QGISSEGDADPDGGLDLEEFsRYLQEREQRLLLMFHSLDR 91
Cdd:cd15897     4 NVFQAVAG-DDGEISATELQQALSNVGWTHFDLGFSletcRSMIAMMDRDHSGKLNFSEF-KGLWNYIKAWQEIFRTYDT 81

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 2462567620  92 NQDGHIDVSEIQQSFRALGISISlEQAEKILHSMDRDGTMTIDW 135
Cdd:cd15897    82 DGSGTIDSNELRQALSGAGYRLS-EQTYDIIIRRYDRGRGNIDF 124

EF-hand, calcium binding motif, found in reticulocalbin-3 (RCN-3); RCN-3, also termed EF-hand calcium-binding protein RLP49, 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 His-Asp-Glu-Leu (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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462567620  19 EELDSNKDGRVDVHELRQGLARLGGGNPDPGAQQgissegdadpdggldlEEFSRYLQEReqrlllmfhslDRNQDGHID 98
Cdd:cd16230   167 EDLDKNKDGYVQVEEYIADLYSGEPGEEEPAWVQ----------------TERQQFRQFR-----------DLNKDGRLD 219

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 2462567620  99 VSEIQQSFRALGISISLEQAEKILH--SMDRDGTMT 132
Cdd:cd16230   220 GSEVGHWVLPPSQDQPLVEANHLLHesDTDKDGRLS 255

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 2462567620  19 EELDSNKDGRVDVHELrqgLARLGGGNPDPGAQQGISSE-------GDADPDGGLDLEEFSRYL-----QEREQRLLLMF 86
Cdd:cd15899   167 EDLDKNGDGFISLEEF---ISDPYSADENEEEPEWVKVEkerfvelRDKDKDGKLDGEELLSWVdpsnqEIALEEAKHLI 243

                          90
                  ....*....|....*.
gi 2462567620  87 HSLDRNQDGHIDVSEI 102
Cdd:cd15899   244 AESDENKDGKLSPEEI 259

Penta-EF hand, calcium binding motifs, found in sorcin, grancalcin, and similar proteins; The family corresponds to the second group of penta-EF hand (PEF) proteins that includes sorcin, grancalcin, and similar proteins. Sorcin, also termed 22 kDa Ca2+-binding protein, CP-22, or V19, is a soluble resistance-related calcium-binding protein that is expressed in normal mammalian tissues, such as the liver, lungs and heart. It contains a flexible glycine and proline-rich N-terminal extension and five EF-hand motifs that associate with membranes in a calcium-dependent manner. It may harbor three potential Ca2+ binding sites through its EF1, EF2 and EF3 hands. However, binding of only two Ca2+/monomer suffices to trigger the conformational change that exposes hydrophobic regions and leads to interaction with the respective targets. Sorcin forms homodimers through the association of the unpaired EF5 hand. Among the PEF proteins, sorcin is unique in that it contains potential phosphorylation sites by cAMP-dependent protein kinase (PKA), and it can form a tetramer at slightly acid pH values although remaining a stable dimer at neutral pH. Grancalcin (GCA) is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It can strongly interact with sorcin to form a heterodimer and further modulate the function of sorcin. GCA exists as homodimers in solution. It contains five EF-hand motifs attached to an N-terminal region of an approximately 50 residue-long segment rich in glycines and prolines. In contrast with sorcin, GCA binds two Ca2+ ions through its EF1 and EF3 hands.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462567620  26 DGRVDVHELRQGLARLG-GGNPDPgaqqgISSEG--------DADPDGGLDLEEFSRYLQEREQrLLLMFHSLDRNQDGH 96
Cdd:cd16181    13 DGQIDADELQRCLTQSGiSGNYQP-----FSLETcrlmiamlDRDHSGKMGFNEFKELWAALNQ-WKTTFMQYDRDRSGT 86

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 2462567620  97 IDVSEIQQSFRALGISISLEQAEKILHSMDRDGTMTID 134
Cdd:cd16181    87 VEPQELQQAIRSFGYNLSPQALNVIVKRYSKNGRITFD 124

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462567620  16 RLFEELDSNKDGRV------------------DVHELRQGLARLGGgnpDPGAQQGIS------SEGDADPDGGLDLEEF 71
Cdd:cd16225    77 QIFKAVDTDKDGNVsweeyrvhfllskgyseeEAEEKIKNNEELKL---DEDDKEVLDrykdrwSQADEPEDGLLDVEEF 153

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 2462567620  72 SRYLQEREQRLLL------MFHSLDRNQDGHIDVSEiqqsFRALGISISLEQAEK 120
Cdd:cd16225   154 LSFRHPEHSRGMLknmvkeILHDLDQDGDEKLTLDE----FVSLPPGTVEEQQAE 204

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 2462567620  67 DLEEFSRYLQEREQ-RLLLMFHSLDRNQDGHIDVSE----IQQSFRalgiSISLEQAEKILHSMDRDGTMTIDWQEWRDH 141
Cdd:cd16224    22 DADEFAKLSPEEQQkRLKSIIKKIDTDSDGFLTEEElsswIQQSFR----HYALEDAKQQFPEYDKDGDGAVTWDEYNMQ 97

                          90       100
                  ....*....|....*....|....*.
gi 2462567620 142 FLLHSLENVEDvlyfwkhsTVLDIGE 167
Cdd:cd16224    98 MYDRVIDYDED--------TVLDDEE 115

EF-hand motif found in phosphoinositide phospholipase C eta (PI-PLC-eta); PI-PLC-eta isozymes represent a class of neuron-specific metazoan PI-PLCs that are most abundant in the brain, particularly in the hippocampus, habenula, olfactory bulb, cerebellum, and throughout the cerebral cortex. They are phosphatidylinositol 4,5-bisphosphate-hydrolyzing enzymes that are more sensitive to Ca2+ than other PI-PLC isozymes. They function as calcium sensors activated by small increases in intracellular calcium concentrations. They are also activated through G-protein-coupled receptor (GPCR) stimulation, and further mediate GPCR signalling pathways. PI-PLC-eta isozymes contain an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core domain, a C2 domain, and a unique C-terminal tail that terminates with a PDZ-binding motif, a potential interaction site for other signaling proteins. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. The C-terminal tail harbors a number of proline-rich motifs which may interact with SH3 (Src homology 3) domain-containing proteins, as well as many serine/threonine residues, suggesting possible regulation of interactions by protein kinases/phosphatases. There are two PI-PLC-eta isozymes (1-2). Aside from the PI-PLC-eta isozymes identified in mammals, their eukaryotic homologs are also present in this family.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2462567620  17 LFEELDSNKDGRVDVHELRQGLARLGGGNPDPGAQQgISSEGDADP-DGGLDLEEFSRYLQ----EREQRLLLMFHSldr 91
Cdd:cd16205     5 TFEEADKNGDGLLSIGEILQLMHKLNVNLPRRKVRQ-MFKEADTDDnQGTLDFEEFCAFYKmmstRRELYLLLLSYS--- 80

                          90
                  ....*....|...
gi 2462567620  92 NQDGHIDVSEIQQ 104
Cdd:cd16205    81 NKKDYLTLEDLAR 93

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 2462567620   16 RLFEELDSNKDGRVDVHELRQGLARL 41
Cdd:smart00054   4 EAFRLFDKDGDGKIDFEEFKDLLKAL 29

EF hand;

                          10        20
                  ....*....|....*....|
gi 2462567620  17 LFEELDSNKDGRVDVHELRQ 36
Cdd:pfam13202   4 TFRQIDLNGDGKISKEELRR 23