calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15231073    1 MADAFTDEQIQEFYEAFCLIDKDSDGFITKEKLTKVMKSMGKNPKAEQLQQMMSDVDIFGNGGITFDDFLYIMAQNTSQE 80
Cdd:PTZ00184   1 MADQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKMKDT 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 15231073   81 SASDELIEVFRVFDRDGDGLISQLELGEGMKDMGMKITAEEAEHMVREADLDGDGFLSFHEFSKMMIA 148
Cdd:PTZ00184  81 DSEEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMMS 148

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15231073    1 MADAFTDEQIQEFYEAFCLIDKDSDGFITKEKLTKVMKSMGKNPKAEQLQQMMSDVDIFGNGGITFDDFLYIMAQNTSQE 80
Cdd:PTZ00184   1 MADQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKMKDT 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 15231073   81 SASDELIEVFRVFDRDGDGLISQLELGEGMKDMGMKITAEEAEHMVREADLDGDGFLSFHEFSKMMIA 148
Cdd:PTZ00184  81 DSEEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMMS 148

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 15231073  85 ELIEVFRVFDRDGDGLISQLELGEGMKDMGMKITAEEAEHMVREADLDGDGFLSFHEFSKMM 146
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15231073   15 EAFCLIDKDSDGFITKEKLTKVMKS----MGKNPKAEQLQQMMSDVDIFGNGGITFDDFlyiMAQNTSQESASDELiEVF 90
Cdd:NF041410  67 ELFSDLDSDGDGSLSSDELAAAAPPppppPDQAPSTELADDLLSALDTDGDGSISSDEL---SAGLTSAGSSADSS-QLF 142

                         90       100
                 ....*....|....*....|.
gi 15231073   91 RVFDRDGDGLISQLELGEGMK 111
Cdd:NF041410 143 SALDSDGDGSVSSDELAAALQ 163

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 15231073   88 EVFRVFDRDGDGLISQLELGEGM---KDMGMKITAEEAehmVREADLDGDGFLSFHEFSKMM 146
Cdd:NF041410  31 QLFAKLDSDGDGSVSQDELSSALsskSDDGSLIDLSEL---FSDLDSDGDGSLSSDELAAAA 89

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15231073    1 MADAFTDEQIQEFYEAFCLIDKDSDGFITKEKLTKVMKSMGKNPKAEQLQQMMSDVDIFGNGGITFDDFLYIMAQNTSQE 80
Cdd:PTZ00184   1 MADQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLMARKMKDT 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 15231073   81 SASDELIEVFRVFDRDGDGLISQLELGEGMKDMGMKITAEEAEHMVREADLDGDGFLSFHEFSKMMIA 148
Cdd:PTZ00184  81 DSEEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMMS 148

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15231073   7 DEQIQEFYEAFCLIDKDSDGFITKEKLTKVMKSMgknpkaeqLQQMMSDVDIFGNGGITFDDFLYIMAqNTSQESASDEL 86
Cdd:COG5126   1 DLQRRKLDRRFDLLDADGDGVLERDDFEALFRRL--------WATLFSEADTDGDGRISREEFVAGME-SLFEATVEPFA 71

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 15231073  87 IEVFRVFDRDGDGLISQLELGEGMKDMGmkITAEEAEHMVREADLDGDGFLSFHEFSKMM 146
Cdd:COG5126  72 RAAFDLLDTDGDGKISADEFRRLLTALG--VSEEEADELFARLDTDGDGKISFEEFVAAV 129

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 15231073  12 EFYEAFCLIDKDSDGFITKEKLTKVMKSMGKNPKAEQLQQMMSDVDIFGNGGITFDDFLYIMA 74
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 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 15231073  21 DKDSDGFITKEKLTKvMKSMGKNPKAEQ--LQQMMSDVDIFGNGGITFDDFLYIM----AQNTSQESASDELIEVFRVFD 94
Cdd:cd15899 133 DQDGDLILTLEEFLA-FLHPEESPYMLDfvIKETLEDLDKNGDGFISLEEFISDPysadENEEEPEWVKVEKERFVELRD 211

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 15231073  95 RDGDGLISQLELGEGMKDMGMKITAEEAEHMVREADLDGDGFLSFHE 141
Cdd:cd15899 212 KDKDGKLDGEELLSWVDPSNQEIALEEAKHLIAESDENKDGKLSPEE 258

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 15231073    10 IQEFYEAFCLIDKDSDGFITKEKLTKVMKS--MGKNPKAEQLQQMMSDVDIFGNGGITFDDFLYIM 73
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKleEGEPLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

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 15231073  12 EFYEAFCLIDKDSDGFITKEKLTKVMKSMGKNP-KAEQLQQMMSDVDIFGNGGITFDDFL----YIMAQNtsqesasdel 86
Cdd:cd16180   1 ELRRIFQAVDRDRSGRISAKELQRALSNGDWTPfSIETVRLMINMFDRDRSGTINFDEFVglwkYIQDWR---------- 70

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 15231073  87 iEVFRVFDRDGDGLISQLELGEGMKDMGMKITAEEAEHMVREADLDGDGFLSFHEFSKMMI 147
Cdd:cd16180  71 -RLFRRFDRDRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDFVEACV 130

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 15231073  12 EFYEAFCLIDKDsDGFITKEKLTKVMKSMGKNPKA-----EQLQQMMSDVDIFGNGGITFDDFLYIMAQNTSQEsasdel 86
Cdd:cd15897   1 QLRNVFQAVAGD-DGEISATELQQALSNVGWTHFDlgfslETCRSMIAMMDRDHSGKLNFSEFKGLWNYIKAWQ------ 73

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 15231073  87 iEVFRVFDRDGDGLISQLELGEGMKDMGMKITAEEAEHMVREADlDGDGFLSFHEF 142
Cdd:cd15897  74 -EIFRTYDTDGSGTIDSNELRQALSGAGYRLSEQTYDIIIRRYD-RGRGNIDFDDF 127

centrin; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 15231073    1 MADAFTDEQIQEfyeAFCLIDKDSDGFITKEKLTKVMKSMGKNPKAEQLQQMMSDVDIFGNGGITFDDFLYIMAQNT 77
Cdd:PTZ00183  83 LGERDPREEILK---AFRLFDDDKTGKISLKNLKRVAKELGETITDEELQEMIDEADRNGDGEISEEEFYRIMKKTN 156

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 15231073  21 DKDSDGFITKEKLTKVMKSMGKNPKAEQLQQMMSDVDIFGNGGITFDDFL-----YIMAQNTSQESASDELI-------- 87
Cdd:cd16227  46 DLNDDGFIDRKELKAWILRSFKMLDEEEANERFEEADEDGDGKVTWEEYLadsfgYDDEDNEEMIKDSTEDDlklleddk 125

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 15231073  88 EVFRVFDRDGDGLISQLELG-----EGMKDMgmkiTAEEAEHMVREADLDGDGFLSFHEF 142
Cdd:cd16227 126 EMFEAADLNKDGKLDKTEFSafqhpEEYPHM----HPVLIEQTLRDKDKDNDGFISFQEF 181

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15231073  20 IDKDSDGFITKEKLTKVMKSMGKNPKAEQLQQMMSDVDIFGNGGITFDDFLYIMAQNTSQESASDELIEV---------- 89
Cdd:cd16226  44 IDKNGDGFVTEEELKDWIKYVQKKYIREDVDRQWKEYDPNKDGKLSWEEYKKATYGFLDDEEEDDDLHESykkmirrder 123

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 15231073  90 -FRVFDRDGDGLISQLElgegmkdMGMKITAEEAEHM----VREA----DLDGDGFLSFHEF 142
Cdd:cd16226 124 rWKAADQDGDGKLTKEE-------FTAFLHPEEFPHMrdivVQETlediDKNKDGFISLEEY 178

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 15231073  21 DKDSDGFITKEKLTKVMKSMGKNPKAEQLQQMMSDVDIFGNGGITFDDF--LYIMAQNTsqesasDELIEVFRVFDRDGD 98
Cdd:cd15898  10 DKDGDGKLSLKEIKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFeeLYKSLTER------PELEPIFKKYAGTNR 83

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 15231073  99 GLISQLELGEGMKD-MGMKITAEEAEHMVREADLDG-DGFLSFHEFSKMM 146
Cdd:cd15898  84 DYMTLEEFIRFLREeQGENVSEEECEELIEKYEPEReNRQLSFEGFTNFL 133

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15231073   15 EAFCLIDKDSDGFITKEKLTKVMKS----MGKNPKAEQLQQMMSDVDIFGNGGITFDDFlyiMAQNTSQESASDELiEVF 90
Cdd:NF041410  67 ELFSDLDSDGDGSLSSDELAAAAPPppppPDQAPSTELADDLLSALDTDGDGSISSDEL---SAGLTSAGSSADSS-QLF 142

                         90       100
                 ....*....|....*....|.
gi 15231073   91 RVFDRDGDGLISQLELGEGMK 111
Cdd:NF041410 143 SALDSDGDGSVSSDELAAALQ 163

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15231073   45 KAEQLQQMMSDVDIFGNGGITFDDFLYIMAQNTSQESASDeLIEVFRVFDRDGDGLISQLELGEGMK----DMGMKITAE 120
Cdd:NF041410  25 SQQFQKQLFAKLDSDGDGSVSQDELSSALSSKSDDGSLID-LSELFSDLDSDGDGSLSSDELAAAAPppppPPDQAPSTE 103

                         90       100
                 ....*....|....*....|...
gi 15231073  121 EAEHMVREADLDGDGFLSFHEFS 143
Cdd:NF041410 104 LADDLLSALDTDGDGSISSDELS 126

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
                ....*....|....*....|....*....|....*....|....*....|....*.
gi 15231073  88 EVFRVFDRDGDGLISQLELGEGMkdMGMKITAEEAEHMVREADLDGDGFLSFHEFS 143
Cdd:cd00052   3 QIFRSLDPDGDGLISGDEARPFL--GKSGLPRSVLAQIWDLADTDKDGKLDKEEFA 56

EF-hand, calcium binding motif, found in peflin and similar proteins; Peflin, also termed penta-EF hand (PEF) protein with a long N-terminal hydrophobic domain, or penta-EF hand domain-containing protein 1, 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+. In lower vertebrates, peflin may interact with transient receptor potential N (TRPN1), suggesting a potential role of peflin in fast transducer channel adaptation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15231073  12 EFYEAFCLIDKDSDGFITKEKLTK-VMKSMGKNPKAEQLQQMMSDVDIFGNGGITFDDF--LYIMAQNTSQesasdelie 88
Cdd:cd16184   1 EVQQWFQAVDRDRSGKISAKELQQaLVNGNWSHFNDETCRLMIGMFDKDKSGTIDIYEFqaLWNYIQQWKQ--------- 71

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....
gi 15231073  89 VFRVFDRDGDGLISQLELGEGMKDMGMKITAEEAEHMVREADLDGDGFLSFHEF 142
Cdd:cd16184  72 VFQQFDRDRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRARRSLTLDQF 125

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 15231073  20 IDKDSDGFITKEKLTKVMKSMGKNPKAEQLQQMMSDVDIFGNGGITFDDFLYIM-------AQNTSQESASDELIEVFRV 92
Cdd:cd16224  45 IDTDSDGFLTEEELSSWIQQSFRHYALEDAKQQFPEYDKDGDGAVTWDEYNMQMydrvidyDEDTVLDDEEEESFRQLHL 124

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 15231073  93 FDRdgdgliSQLELGEGMKDMGMKIT-------AEEAEHM--------VREADLDGDGFLSFHEF 142
Cdd:cd16224 125 KDK------KRFDKANTDGGPGLNLTefiafehPEEVDYMtefviqeaLEEHDKDGDGFISLEEF 183

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 15231073   9 QIQEFYEAfclIDKDSDGFITKEKLTKVMKSMGKNPKAEQLQQMMSDVDIFGNGGITFDDF--LYIMAQNTSQesasdel 86
Cdd:cd16185   1 ELRQWFRA---VDRDRSGSIDVNELQKALAGGGLLFSLATAEKLIRMFDRDGNGTIDFEEFaaLHQFLSNMQN------- 70

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 15231073  87 ieVFRVFDRDGDGLISQLELGEGMKDMGMKITAEEAEHMVREADLDGDGFLSFHEFSKMMI 147
Cdd:cd16185  71 --GFEQRDTSRSGRLDANEVHEALAASGFQLDPPAFQALFRKFDPDRGGSLGFDDYIELCI 129

EF-hand, calcium binding motif, found in the hexa-EF hand proteins family; The hexa-EF hand proteins family, also named the calbindin sub-family, contains a group of six EF-hand Ca2+-binding proteins, including calretinin (CR, also termed 29 kDa calbindin), calbindin D28K (CB, also termed vitamin D-dependent calcium-binding protein, avian-type), and secretagogin (SCGN). CR is a cytosolic hexa-EF-hand calcium-binding protein predominantly expressed in a variety of normal and tumorigenic t-specific neurons of the central and peripheral nervous system. It is a multifunctional protein implicated in many biological processes, including cell proliferation, differentiation, and cell death. CB is highly expressed in brain tissue. It is a strong calcium-binding and buffering protein responsible for preventing a neuronal death as well as maintaining and controlling calcium homeostasis. SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a Ca2+ sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. Although the family members share a significant amount of secondary sequence homology, they display altered structural and biochemical characteristics, and operate in distinct fashions. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. They harbor two and four EF-hand motifs, respectively. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. Human SCGN simultaneously binds four calcium ions through its EF-hands 3, 4, 5 and 6 in one high affinity and three low affinity calcium-binding sites. In contrast, SCGNs in other lower eukaryotes, such as D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, are fully competent in terms of six calcium-binding.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15231073  13 FYEAFCLIDKDSDGFITKEKLTKVMKSM-----GKNPKAEQLQQM----MSDVDIFGNGGITFDDFLYIMA--------- 74
Cdd:cd15902   1 FMEVWMHFDADGNGYIEGKELDSFLRELlkalnGKDKTDDEVAEKkkefMEKYDENEDGKIEIRELANILPteenflllf 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15231073  75 QNTSQESASDELIEVFRVFDRDGDGLISQLELGEGMKDMGMKI--------TAEEAEHMVREADLDGDGFLSFHEFSKMM 146
Cdd:cd15902  81 RREQPLISSVEFMKIWRKYDTDGSGFIEAKELKGFLKDLLLKNkkhvsppkLDEYTKLILKEFDANKDGKLELDEMAKLL 160

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 15231073  14 YEAFCLIDKDSDGFITKEKLTKVMkSMGK----NPkaEQLQQMMSDVDIFGNGGITFDDFL----YIMA-QNTsqesasd 84
Cdd:cd16183   3 WNVFQRVDKDRSGQISATELQQAL-SNGTwtpfNP--ETVRLMIGMFDRDNSGTINFQEFAalwkYITDwQNC------- 72

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 15231073  85 elievFRVFDRDGDGLISQLELGEGMKDMGMKITAEEAEHMVREADLDGDGFLSFHEF 142
Cdd:cd16183  73 -----FRSFDRDNSGNIDKNELKQALTSFGYRLSDQFYDILVRKFDRQGRGTIAFDDF 125

EF-hand domain;

                          10        20        30
                  ....*....|....*....|....*....|
gi 15231073    85 ELIEVFRVFDRDGDGLISQLELGEGMKDMG 114
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSLG 30

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
                ....*....|....*....|....*....|....*....|....*....|....
gi 15231073  17 FCLIDKDSDGFITKEKLTKVMKSMGKNPKAEQLQQMMSDVDIfgNGGITFDDFL 70
Cdd:cd16181  76 FMQYDRDRSGTVEPQELQQAIRSFGYNLSPQALNVIVKRYSK--NGRITFDDFV 127

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 15231073  76 NTSQESASDELIEVFRVFDRDGDGLISQLElgegMKDMGMKITAE-------EAEHMVREADLDGDGFLSFHEF 142
Cdd:cd16225  26 EDSEPKKRKKLKEIFKKVDVNTDGFLSAEE----LEDWIMEKTQEhfqeaveENEQIFKAVDTDKDGNVSWEEY 95

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 15231073    60 GNGGITFDDFLYIMAQNTSQESASDELIEVFRVFDRDGDGLISQLELGEGMKD 112
Cdd:pfam13833   1 EKGVITREELKRALALLGLKDLSEDEVDILFREFDTDGDGYISFDEFCVLLER 53

EF-hand, calcium binding motif, found in peflin and similar proteins; Peflin, also termed penta-EF hand (PEF) protein with a long N-terminal hydrophobic domain, or penta-EF hand domain-containing protein 1, 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+. In lower vertebrates, peflin may interact with transient receptor potential N (TRPN1), suggesting a potential role of peflin in fast transducer channel adaptation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15231073  10 IQEFYEAFCLIDKDSDGFITKEKLTKVMKSMGKNPKAEQLQQMMSDVDIFGNGGITFDDFLYIMAQNTSqesasdeLIEV 89
Cdd:cd16184  66 IQQWKQVFQQFDRDRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRARRSLTLDQFIQVCVQLQS-------LTDA 138

                        90
                ....*....|..
gi 15231073  90 FRVFDRDGDGLI 101
Cdd:cd16184 139 FRQRDTQMTGTI 150

phosphatidylserine decarboxylase

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 15231073   89 VFRVFDRDGDGLISQLELGEGMKDMGMKITAEEAEHMVREADLDGDGFLSFHEFSKMM 146
Cdd:PLN02964 184 ILAIVDYDEDGQLSFSEFSDLIKAFGNLVAANKKEELFKAADLNGDGVVTIDELAALL 241

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
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 15231073  88 EVFRVFDRDGDGLISQLELGEGMKDMGMKITAEEAEHMVREADLDGD-GFLSFHEFS---KMM 146
Cdd:cd16220   4 QTFEEADKNGDGLLNIEEIYQLMHKLNVNLPRRKVRQMFQEADTDENqGTLTFEEFCvfyKMM 66

serine/threonine protein phosphatase 2A regulatory subunit B" subunit alpha; Heterotrimeric serine/threonine protein phosphatase 2A (PP2A) consists of scaffolding (A), catalytic (C), and variable (B, B', and B") subunits. The variable subunits dictate subcellular localization and substrate specificity of the PP2A holoenzyme. This group contains protein phosphatase subunit PR130 (also known as protein phosphatase 2A regulatory subunit B'' subunit alpha, PR72, or PPP2R3) that is encoded by the PPP2R3A gene. PR130 and PR72 subunits are derived from the same gene through differential splicing; they harbor specific N-terminal domains of different lengths that are encoded by alternatively spliced exons and have identical C-termini. The common C-terminus contains a two-domain elongated structure with two calcium EF-hands which mediate Ca2+-dependent changes in phosphatase activity. The PR130 subunit has been shown to interact with the LIM domain of lipoma-preferred partner (LPP) through a conserved Zn2+-finger-like motif in the N-terminus of PR130.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15231073   1 MADAFTDEQIQEFYEAFCLIDKDSDGFITKEKLTKVMKSMGKNpkaEQLQQMMSDVDIFGN-----GGITFDDFLYIMAQ 75
Cdd:cd21506 105 ITDYFSYEHFYVIYCKFWELDTDHDLYIDQKDLARYNDQASSS---RIIERIFSGAVTRGNsvqkeGRMSYADFVWFLIS 181

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 15231073  76 NTSQESASDelIEV-FRVFDRDGDGLISQLELG-------EGMKDMGMK 116
Cdd:cd21506 182 EEDKRNPTS--IEYwFRCMDLDGDGVLSMYELEyfyeeqcERMEAMGIE 228