calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15219514   20 ELKKVFDKFDANGDGKISVSELGNVFKSMGTSYTEEELNRVLDEIDIDCDGFINQEEFATI----CRSSSSAVEIREAFD 95
Cdd:PTZ00184  12 EFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLmarkMKDTDSEEEIKEAFK 91

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 15219514   96 LYDQNKNGLISSSEIHKVLNRLGMTCSVEDCVRMIGHVDTDGDGNVNFEEFQKMMSS 152
Cdd:PTZ00184  92 VFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMMS 148

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15219514   20 ELKKVFDKFDANGDGKISVSELGNVFKSMGTSYTEEELNRVLDEIDIDCDGFINQEEFATI----CRSSSSAVEIREAFD 95
Cdd:PTZ00184  12 EFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLmarkMKDTDSEEEIKEAFK 91

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 15219514   96 LYDQNKNGLISSSEIHKVLNRLGMTCSVEDCVRMIGHVDTDGDGNVNFEEFQKMMSS 152
Cdd:PTZ00184  92 VFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMMS 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 15219514  89 EIREAFDLYDQNKNGLISSSEIHKVLNRLGMTCSVEDCVRMIGHVDTDGDGNVNFEEFQKMMS 151
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15219514    8 STNKSTTPSTDME--LKKVFDKFDANGDGKISVSELGNVFKSMGTSYTEEELNRVLDEIDIDCDGFINQEEFATICRSSS 85
Cdd:NF041410  14 STSSSSTSSARSQqfQKQLFAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAPPPP 93

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 15219514   86 SAVEIREAFDL-------YDQNKNGLISSSEIHKVLNRLGmtcSVEDCVRMIGHVDTDGDGNVNFEEFQKMMSSPE 154
Cdd:NF041410  94 PPPDQAPSTELaddllsaLDTDGDGSISSDELSAGLTSAG---SSADSSQLFSALDSDGDGSVSSDELAAALQPPP 166

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15219514   20 ELKKVFDKFDANGDGKISVSELGNVFKSMGTSYTEEELNRVLDEIDIDCDGFINQEEFATI----CRSSSSAVEIREAFD 95
Cdd:PTZ00184  12 EFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLmarkMKDTDSEEEIKEAFK 91

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 15219514   96 LYDQNKNGLISSSEIHKVLNRLGMTCSVEDCVRMIGHVDTDGDGNVNFEEFQKMMSS 152
Cdd:PTZ00184  92 VFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEFVKMMMS 148

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15219514   20 ELKKVFDKFDANGDGKISVSELGNVFKSMGTSYTEEELNRVLDEIDIDCDGFINQEEFATICRSS----SSAVEIREAFD 95
Cdd:PTZ00183  18 EIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMTKKlgerDPREEILKAFR 97

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 15219514   96 LYDQNKNGLISSSEIHKVLNRLGMTCSVEDCVRMIGHVDTDGDGNVNFEEFQKMM 150
Cdd:PTZ00183  98 LFDDDKTGKISLKNLKRVAKELGETITDEELQEMIDEADRNGDGEISEEEFYRIM 152

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 15219514  20 ELKKVFDKFDANGDGKISVSELGNVFKSMGTSYTEEELNRVLDEIDIDCDGFINQEEFATI 80
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLEL 61

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 15219514    18 DMELKKVFDKFDANGDGKISVSELGNVFKS--MGTSYTEEELNRVLDEIDIDCDGFINQEEFATICR 82
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKleEGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

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 15219514  20 ELKKVFDKFDANGDGKISVSELGNVFKSMGTSYTEEELNRVLDEIDIDCDGFINQEEFATICRSSSSaveIREAFDLYDQ 99
Cdd:cd16185   1 ELRQWFRAVDRDRSGSIDVNELQKALAGGGLLFSLATAEKLIRMFDRDGNGTIDFEEFAALHQFLSN---MQNGFEQRDT 77

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 15219514 100 NKNGLISSSEIHKVLNRLGMTCSVEDCVRMIGHVDTDGDGNVNFEEF 146
Cdd:cd16185  78 SRSGRLDANEVHEALAASGFQLDPPAFQALFRKFDPDRGGSLGFDDY 124

calmodulin; Provisional

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 15219514   10 NKSTTPSTDMELKKVFDKFDANGDGKISVSELGNVFKSMGTSYTEEELNRVLDEIDIDCDGFINQEEF 77
Cdd:PTZ00184  75 RKMKDTDSEEEIKEAFKVFDRDGNGFISAAELRHVMTNLGEKLTDEEVDEMIREADVDGDGQINYEEF 142

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15219514    8 STNKSTTPSTDME--LKKVFDKFDANGDGKISVSELGNVFKSMGTSYTEEELNRVLDEIDIDCDGFINQEEFATICRSSS 85
Cdd:NF041410  14 STSSSSTSSARSQqfQKQLFAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAPPPP 93

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 15219514   86 SAVEIREAFDL-------YDQNKNGLISSSEIHKVLNRLGmtcSVEDCVRMIGHVDTDGDGNVNFEEFQKMMSSPE 154
Cdd:NF041410  94 PPPDQAPSTELaddllsaLDTDGDGSISSDELSAGLTSAG---SSADSSQLFSALDSDGDGSVSSDELAAALQPPP 166

EF-hand motif found in phosphoinositide phospholipase C delta (PI-PLC-delta); PI-PLC-delta isozymes represent a class of metazoan PI-PLCs that are some of the most sensitive to calcium among all PLCs. Their activation is modulated by intracellular calcium ion concentration, phospholipids, polyamines, and other proteins, such as RhoAGAP. Like other PI-PLC isozymes, PI-PLC-delta isozymes contain 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 C-terminal C2 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. There are three PI-PLC-delta isozymes (1, 3 and 4). PI-PLC-delta1 is relatively well characterized. It is activated by high calcium levels generated by other PI-PLC family members, and therefore functions as a calcium amplifier within the cell. Different PI-PLC-delta isozymes have different tissue distribution and different subcellular locations. PI-PLC-delta1 is mostly a cytoplasmic protein, PI-PLC-delta3 is located in the membrane, and PI-PLC-delta4 is predominantly detected in the cell nucleus. PI-PLC-delta isozymes is evolutionarily conserved even in non-mammalian species, such as yeast, slime molds and plants.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15219514  21 LKKVFDKFDANGDGKISVSELGNVFKSMGTSYTEEELNRVLDEIDIDCDGFINQEEFATICRSSSSAVEIREAFDLYDQN 100
Cdd:cd16202   2 LKDQFRKADKNGDGKLSFKECKKLLKKLNVKVDKDYAKKLFQEADTSGEDVLDEEEFVQFYNRLTKRPEIEELFKKYSGD 81

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 15219514 101 KnGLISSSEIHKVLNR-LGMTCS-VEDCVRMIGHVDTDGDGNVN----FEEFQKMMSSPE 154
Cdd:cd16202  82 D-EALTVEELRRFLQEeQKVKDVtLEWAEQLIETYEPSEDLKAQglmsLDGFTLFLLSPD 140

EF-hand, calcium binding motif, found in parvalbumin-like EF-hand family; The family includes alpha- and beta-parvalbumins, and a group of uncharacterized calglandulin-like proteins. Parvalbumins are small, acidic, cytosolic EF-hand-containing Ca2+-buffer and Ca2+ transporter/shuttle proteins belonging to EF-hand superfamily. They are expressed by vertebrates in fast-twitch muscle cells, specific neurons of the central and peripheral nervous system, sensory cells of the mammalian auditory organ (Corti's cell), and some other cells, and characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Thus, they may play an additional role in Mg2+ handling. Moreover, parvalbumins represent one of the major animal allergens. In metal-bound states, parvalbumins possess a rigid and stable tertiary structure and display strong allergenicity. In contrast, the metal-free parvalbumins are intrinsically disordered, and the loss of metal ions results in a conformational change that decreases their IgE binding capacity. Furthermore, parvalbumins have been widely used as a neuronal marker for a variety of functional brain systems. They also function as a Ca2+ shuttle transporting Ca2+ from troponin-C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus they may facilitate myocardial relaxation and play important roles in cardiac diastolic dysfunction. Parvalbumins consists of alpha- and beta- sublineages, which can be distinguished on the basis of isoelectric point (pI > 5 for alpha; pI

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15219514  67 DCDGFINQEEFATICRSSSSAVEIREAFDLYDQNKNGLISSSEIHKVLNRL---GMTCSVEDCVRMIGHVDTDGDGNVNF 143
Cdd:cd16251  13 AHGSFNYKKFFEHVGLKQKSEDQIKKVFQILDKDKSGFIEEEELKYILKGFsiaGRDLTDEETKALLAAGDTDGDGKIGV 92

                ....*.
gi 15219514 144 EEFQKM 149
Cdd:cd16251  93 EEFATL 98

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        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15219514  20 ELKKVFDKFdANGDGKISVSELGNVFKS--MGTSYTEEELNR-----VLDEIDIDCDGFINQEEFATIcrsSSSAVEIRE 92
Cdd:cd16182   1 QVRELFEKL-AGEDEEIDAVELQKLLNAslLKDMPKFDGFSLetcrsLIALMDTNGSGRLDLEEFKTL---WSDLKKWQA 76

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....
gi 15219514  93 AFDLYDQNKNGLISSSEIHKVLNRLGMTCSvEDCVRMIGHVDTDGDGNVNFEEF 146
Cdd:cd16182  77 IFKKFDTDRSGTLSSYELRKALESAGFHLS-NKVLQALVLRYADSTGRITFEDF 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 15219514  20 ELKKVFDKFDANGDGKISVSELGNVFKSM----GTSY----TEEELNRVLDEIDIDCDGFINQEEFATIC---------- 81
Cdd:cd15902  91 EFMKIWRKYDTDGSGFIEAKELKGFLKDLllknKKHVsppkLDEYTKLILKEFDANKDGKLELDEMAKLLpvqenfllkf 170

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 15219514  82 RSSSSAVEIR----EAFDLYDQNKNGLISSSEIHKVLNRLG------MTCSVEDCVR--MIGHVDTDGDGNVNFEE 145
Cdd:cd15902 171 QILGAMDLTKedfeKVFEHYDKDNNGVIEGNELDALLKDLLeknkadIDKPDLENFRdaILRACDKNKDGKIQKTE 246

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 15219514  83 SSSSAVEIREAFDLYDQNKNGLISSSEIHKVLNRLGMTCSV-----EDCVRMIGHVDTDGDGNVNFEEFQKMMSS 152
Cdd:cd16252  32 SEQQEEAIRKAFQMLDKDKSGFIEWNEIKYILSTVPSSMPVaplsdEEAEAMIQAADTDGDGRIDFQEFSDMVKK 106

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 15219514  21 LKKVFDKFDANGDGKISVSELGNVFKSMGTSYTEEELNRVLDEIDIDCDGFINQEEFaticrssssaveIREAFDLYDQN 100
Cdd:cd16226  37 LGIIVDKIDKNGDGFVTEEELKDWIKYVQKKYIREDVDRQWKEYDPNKDGKLSWEEY------------KKATYGFLDDE 104

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*.
gi 15219514 101 KNGLISSSEIHKVLNRlgmtcsveDCVRMIgHVDTDGDGNVNFEEF 146
Cdd:cd16226 105 EEDDDLHESYKKMIRR--------DERRWK-AADQDGDGKLTKEEF 141

Eps15 homology domain; Pair of EF hand motifs that recognise proteins containing Asn-Pro-Phe (NPF) sequences.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 15219514     23 KVFDKFDANGDGKISVSELGNVFKSMGTSYTEeeLNRVLDEIDIDCDGFINQEEFATICR 82
Cdd:smart00027  14 QIFRSLDKNQDGTVTGAQAKPILLKSGLPQTL--LAKIWNLADIDNDGELDKDEFALAMH 71

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 15219514    54 EEELNRVLDEIDIDCDGFINQEEFATICRSSSSAV-----EIREAFDLYDQNKNGLISSSEIHKVL 114
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEplsdeEVEELFKEFDLDKDGRISFEEFLELY 66

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 15219514  21 LKKVFDKFDANGDGKISVSELGNVFKSMGTSYTEEELNRVLDEIDIDCDGFINQEEFAT------ICRSSSSAVEIREA- 93
Cdd:cd15899  37 LGVIVSKMDVDKDGFISAKELHSWILESFKRHAMEESKEQFRAVDPDEDGHVSWDEYKNdtygsvGDDEENVADNIKEDe 116

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15219514  94 ------------FDLYDQNKNGLISSSE----IHKVLNRLGMTCSVEDCVRMIghvDTDGDGNVNFEEFQKMMSS----- 152
Cdd:cd15899 117 eykklllkdkkrFEAADQDGDLILTLEEflafLHPEESPYMLDFVIKETLEDL---DKNGDGFISLEEFISDPYSadene 193

                ....*..
gi 15219514 153 --PELVK 157
Cdd:cd15899 194 eePEWVK 200

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 15219514     20 ELKKVFDKFDANGDGKISVSELGNVFKSM 48
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

EF hand;

                          10        20
                  ....*....|....*....|....
gi 15219514    21 LKKVFDKFDANGDGKISVSELGNV 44
Cdd:pfam13202   1 LKDTFRQIDLNGDGKISKEELRRL 24

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.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15219514  23 KVFDKFDANGDGKISVSELGNVFKSM-----GTSYTEEEL----NRVLDEIDIDCDGFINQEEFATI------------- 80
Cdd:cd15902   3 EVWMHFDADGNGYIEGKELDSFLRELlkalnGKDKTDDEVaekkKEFMEKYDENEDGKIEIRELANIlpteenflllfrr 82

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 15219514  81 CRSSSSAVEIREAFDLYDQNKNGLISSSEIHKVLNRL---GMTCSVEDCVR-----MIGHVDTDGDGNVNFEEFQKMM 150
Cdd:cd15902  83 EQPLISSVEFMKIWRKYDTDGSGFIEAKELKGFLKDLllkNKKHVSPPKLDeytklILKEFDANKDGKLELDEMAKLL 160

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 15219514  21 LKKVFDKFDANGDGKISVSELGNVFKSMGTSYTEEELNRVLDEIDID-CDGFINQEEFATICRSSSSAVEIREAFDLYDQ 99
Cdd:cd16205   2 LKQTFEEADKNGDGLLSIGEILQLMHKLNVNLPRRKVRQMFKEADTDdNQGTLDFEEFCAFYKMMSTRRELYLLLLSYSN 81

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 15219514 100 NKNGLISSSEIHKVLNRLGMT-CSVEDCVRMIGHVDTDGDGNVN----FEEFQKMMSSPE 154
Cdd:cd16205  82 KKDYLTLEDLARFLEVEQKMTnVTLEYCLDIIEKFEPSEENKKNgllgIDGFTNYMRSPA 141

EF-hand, calcium binding motif, found in parvalbumin-like EF-hand family; The family includes alpha- and beta-parvalbumins, and a group of uncharacterized calglandulin-like proteins. Parvalbumins are small, acidic, cytosolic EF-hand-containing Ca2+-buffer and Ca2+ transporter/shuttle proteins belonging to EF-hand superfamily. They are expressed by vertebrates in fast-twitch muscle cells, specific neurons of the central and peripheral nervous system, sensory cells of the mammalian auditory organ (Corti's cell), and some other cells, and characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Thus, they may play an additional role in Mg2+ handling. Moreover, parvalbumins represent one of the major animal allergens. In metal-bound states, parvalbumins possess a rigid and stable tertiary structure and display strong allergenicity. In contrast, the metal-free parvalbumins are intrinsically disordered, and the loss of metal ions results in a conformational change that decreases their IgE binding capacity. Furthermore, parvalbumins have been widely used as a neuronal marker for a variety of functional brain systems. They also function as a Ca2+ shuttle transporting Ca2+ from troponin-C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus they may facilitate myocardial relaxation and play important roles in cardiac diastolic dysfunction. Parvalbumins consists of alpha- and beta- sublineages, which can be distinguished on the basis of isoelectric point (pI > 5 for alpha; pI

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 15219514  17 TDMELKKVFDKFDANGDGKISVSELGNV---FKSMGTSYTEEELNRVLDEIDIDCDGFINQEEFATIC 81
Cdd:cd16251  32 SEDQIKKVFQILDKDKSGFIEEEELKYIlkgFSIAGRDLTDEETKALLAAGDTDGDGKIGVEEFATLV 99

EF-hand, calcium binding motif, found in secretagogin (SCGN); 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 calcium sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. It also serves as a calcium buffer in neurons. Thus, SCGN may be linked to the pathogenesis of neurological diseases such as Alzheimer's, and also acts as a serum marker of neuronal damage, or as a tumor biomarker. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. All six EF hand motifs of SCGN in some eukaryotes, including D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, could potentially bind six calcium ions. In contrast, SCGNs from higher eukaryotes have at least one non-functional EF-hand motif due to the mutation(s) or deletions. For instance, the EF1 loop does not coordinate calcium ion due to the key residue asparagine replaced by lysine in SCGNs of many mammalian species. Moreover, the EF2 loop seems to be competent for calcium-binding in most mammalian SCGNs except for human and chimpanzee orthologs.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15219514  12 STTPSTDMELKKVFDKF----DANGDGKISVSELGNVFKSMGTSY-----TEEELN------RVLDEIDIDCDGFINQEE 76
Cdd:cd16178  34 TKDTISADEVQDVKECFmsayDVTGDGRIQIQELANIILPDDENFllffrREEPLDssvefmRIWRKYDADSSGYISAAE 113

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 15219514  77 FATICR-------SSSSAVEIREAFD----LYDQNKNGLISSSEIHKVLN 115
Cdd:cd16178 114 LKNFLRdlflqhkKVITEDKLDEYTDtmmkIFDKNKDGRLDLNDMARILA 163

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
                ....*....|....*....|....*....|....*....|....*....|.
gi 15219514  98 DQNKNGLISSSEIHKVLNRLGMTCSVEDCVR-MIGHVDTDGDGNVNFEEFQ 147
Cdd:cd16183  10 DKDRSGQISATELQQALSNGTWTPFNPETVRlMIGMFDRDNSGTINFQEFA 60

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 15219514    128 RMIGHVDTDGDGNVNFEEFQKMMSS 152
Cdd:smart00054   4 EAFRLFDKDGDGKIDFEEFKDLLKA 28

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 15219514  92 EAFDLYDQNKNGLISSSEIHKVLNRLGMTCSVedcvrmIGHV----DTDGDGNVNFEEF 146
Cdd:cd00052   3 QIFRSLDPDGDGLISGDEARPFLGKSGLPRSV------LAQIwdlaDTDKDGKLDKEEF 55

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 15219514  20 ELKKVFDKFDAnGDGKISVSELGNVFKSMGTSYTEEELNRVLDEI-----DIDCDGFINQEEFATICRSSSSaveIREAF 94
Cdd:cd15897   1 QLRNVFQAVAG-DDGEISATELQQALSNVGWTHFDLGFSLETCRSmiammDRDHSGKLNFSEFKGLWNYIKA---WQEIF 76

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 15219514  95 DLYDQNKNGLISSSEIHKVLNRLGMTCSvEDCVRMIGHVDTDGDGNVNFEEF 146
Cdd:cd15897  77 RTYDTDGSGTIDSNELRQALSGAGYRLS-EQTYDIIIRRYDRGRGNIDFDDF 127

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

                        10        20        30
                ....*....|....*....|....*....|....
gi 15219514  17 TDMELKKVFDKFDANGDGKISVSELGNVFKSMGT 50
Cdd:COG5126 101 SEEEADELFARLDTDGDGKISFEEFVAAVRDYYT 134

EF hand; The EF-hands can be divided into two classes: signalling proteins and buffering/transport proteins. The first group is the largest and includes the most well-known members of the family such as calmodulin, troponin C and S100B. These proteins typically undergo a calcium-dependent conformational change which opens a target binding site. The latter group is represented by calbindin D9k and do not undergo calcium dependent conformational changes.

                          10        20
                  ....*....|....*....|....*...
gi 15219514   125 DCVRMIGHVDTDGDGNVNFEEFQKMMSS 152
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKK 28

Calcium-activated neutral; CAPN3, also termed calcium-activated neutral proteinase 3 (CANP 3), or calpain L3, or calpain p94, or muscle-specific calcium-activated neutral protease 3, or new calpain 1 (nCL-1), is a calpain large subunit that is mainly expressed in skeletal muscle, or lens. The skeletal muscle-specific CAPN3 are pathologically associated with limb girdle muscular dystrophy type 2A (LGMD2A). Its autolytic activity can be positively regulated by calmodulin (CaM), a known transducer of the calcium signal. CAPN3 is also involved in human melanoma tumorigenesis and progression. It impairs cell proliferation and stimulates oxidative stress-mediated cell death in melanoma cells. Moreover, it plays an important role in sarcomere remodeling and mitochondrial protein turnover. Furthermore, the phosphorylated skeletal muscle-specific CAPN3 acts as a myofibril structural component and may participate in myofibril-based signaling pathways. In the eye, the lens-specific CAPN3, together with CAPN2, is responsible for proteolytic cleavages of alpha and beta-crystallin. Overactivated alpha and beta-crystallin can lead to cataract formation. CAPN3 exists as a homodimer, rather than a heterodimer with the calpain small subunit. It may also form heterodimers with other calpain large subunits. CAPN3 contains a long N-terminal region, 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. Ca2+ binding at EF5 of the CAPN3 PEF domain is a distinct feature not observed in other calpain isoforms.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*
gi 15219514 105 ISSSEIHKVLNRL----------GMTcsVEDCVRMIGHVDTDGDGNVNFEEFQKM 149
Cdd:cd16190  16 ISADELRSVLNRVvkkhkdlkteGFT--LESCRSMIALMDTDGSGKLNLQEFRHL 68

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
                ....*....|....*....|....*....|....*....|....*....|...
gi 15219514  98 DQNKNGLISSSEIHKVL-NRLGMTCSVEDCVRMIGHVDTDGDGNVNFEEFQKM 149
Cdd:cd16184  10 DRDRSGKISAKELQQALvNGNWSHFNDETCRLMIGMFDKDKSGTIDIYEFQAL 62