calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920728  11 MCSNFDAYELRRLTRRFKKLDVDGSGSLSVEEF-MSLPELQQNPL---VQRVIDIFDEDGNGEVDFREFIQGISQFSVKG 86
Cdd:PTZ00184   1 MADQLTEEQIAEFKEAFSLFDKDGDGTITTKELgTVMRSLGQNPTeaeLQDMINEVDADGNGTIDFPEFLTLMARKMKDT 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 392920728  87 DKNTKLKFAFRIYDMDRDGFISNGELFQVLKMMvGNNLKDSQlqqiVDKTILFHDKDGDGKISFQEFC 154
Cdd:PTZ00184  81 DSEEEIKEAFKVFDRDGNGFISAAELRHVMTNL-GEKLTDEE----VDEMIREADVDGDGQINYEEFV 143

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 392920728   90 TKLKFAFRIYDMDRDGFISNGELFQVLKM-MVGNNLKDSQLQQIVDKtilfHDKDGDGKISFQEFCDVV 157
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKlEEGEPLSDEEVEELFKE----FDLDKDGRISFEEFLELY 66

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

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 392920728    91 KLKFA--FRIYDMDRDGFISNGelfQVLKMMVGNNLKDSQLQQIVDktilFHDKDGDGKISFQEFC 154
Cdd:smart00027   9 KAKYEqiFRSLDKNQDGTVTGA---QAKPILLKSGLPQTLLAKIWN----LADIDNDGELDKDEFA 67

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920728  11 MCSNFDAYELRRLTRRFKKLDVDGSGSLSVEEF-MSLPELQQNPL---VQRVIDIFDEDGNGEVDFREFIQGISQFSVKG 86
Cdd:PTZ00184   1 MADQLTEEQIAEFKEAFSLFDKDGDGTITTKELgTVMRSLGQNPTeaeLQDMINEVDADGNGTIDFPEFLTLMARKMKDT 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 392920728  87 DKNTKLKFAFRIYDMDRDGFISNGELFQVLKMMvGNNLKDSQlqqiVDKTILFHDKDGDGKISFQEFC 154
Cdd:PTZ00184  81 DSEEEIKEAFKVFDRDGNGFISAAELRHVMTNL-GEKLTDEE----VDEMIREADVDGDGQINYEEFV 143

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920728  27 FKKLDVDGSGSLSVEEF----MSLPELQQNPLVQRVIDIFDEDGNGEVDFREFIQGISQFSVKGDKNTKLKFAFRIYDMD 102
Cdd:PTZ00183  23 FDLFDTDGSGTIDPKELkvamRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMTKKLGERDPREEILKAFRLFDDD 102

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 392920728 103 RDGFISNGELFQVLKMMvGNNLKDSQLQQIVDktilFHDKDGDGKISFQEFCDVVEHT 160
Cdd:PTZ00183 103 KTGKISLKNLKRVAKEL-GETITDEELQEMID----EADRNGDGEISEEEFYRIMKKT 155

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 392920728  27 FKKLDVDGSGSLSVeefmslPELQQ-----NPL-----VQRVIDIFDEDGNGEVDFREFiQGISQFSvkgdknTKLKFAF 96
Cdd:cd16185    6 FRAVDRDRSGSIDV------NELQKalaggGLLfslatAEKLIRMFDRDGNGTIDFEEF-AALHQFL------SNMQNGF 72

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 392920728  97 RIYDMDRDGFISNGELFQVLKmMVGNNLKDSQLQQIVDKtilfHDKDGDGKISFQEF 153
Cdd:cd16185   73 EQRDTSRSGRLDANEVHEALA-ASGFQLDPPAFQALFRK----FDPDRGGSLGFDDY 124

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 392920728  22 RLTRRFKKLDVDGSGSLSVEEFM----SLPELQQNPLVQRVIDIFDEDGNGEVDFREFIQGIS 80
Cdd:cd00051    1 ELREAFRLFDKDGDGTISADELKaalkSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

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 392920728  27 FKKLDVDGSGSLSVEEfmslpeLQQ----------NPLVQR-VIDIFDEDGNGEVDFREFiQGISQFSvkgdknTKLKFA 95
Cdd:cd16183    6 FQRVDKDRSGQISATE------LQQalsngtwtpfNPETVRlMIGMFDRDNSGTINFQEF-AALWKYI------TDWQNC 72

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 392920728  96 FRIYDMDRDGFISNGELFQVLKMMvGNNLKDSQLQQIVDKtilfHDKDGDGKISFQEF--CDVVEHT 160
Cdd:cd16183   73 FRSFDRDNSGNIDKNELKQALTSF-GYRLSDQFYDILVRK----FDRQGRGTIAFDDFiqCCVVLQT 134

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 392920728  20 LRRLTRRFKKLDVDGSGSLSVEEFMSLPELQQNP-----LVQRVIDIFDEDGNGEVDFREFIQGIsqfsVKGDKNT---- 90
Cdd:cd15899  122 LLKDKKRFEAADQDGDLILTLEEFLAFLHPEESPymldfVIKETLEDLDKNGDGFISLEEFISDP----YSADENEeepe 197

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 392920728  91 -----KLKFAfRIYDMDRDGFISNGELfqvLKMMVGNNlkDSQLQQIVDKTILFHDKDGDGKISFQEfcdVVEHTE 161
Cdd:cd15899  198 wvkveKERFV-ELRDKDKDGKLDGEEL---LSWVDPSN--QEIALEEAKHLIAESDENKDGKLSPEE---ILDNHE 264

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 392920728  27 FKKLDVDGSGSLSVEE---FMSLPELQQNPLV---------QRVIDIFDEDGNGEVDFREFIQGIS-------QFSVKGD 87
Cdd:cd15902   96 WRKYDTDGSGFIEAKElkgFLKDLLLKNKKHVsppkldeytKLILKEFDANKDGKLELDEMAKLLPvqenfllKFQILGA 175

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 392920728  88 KNTK---LKFAFRIYDMDRDGFISNGELFQVLKMMVGNNLKDSQLQQIVD--KTIL-FHDKDGDGKISFQEFCDV 156
Cdd:cd15902  176 MDLTkedFEKVFEHYDKDNNGVIEGNELDALLKDLLEKNKADIDKPDLENfrDAILrACDKNKDGKIQKTELALF 250

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 392920728  68 GEVDFREFIQGISQFSVKGDKNTKLKFAFRIYDMDRDGFISNGELFQVLKMMVGNN----LKDSQLQQIVDKTilfhDKD 143
Cdd:cd16252   15 GSFNYSKFFEYMQKFQTSEQQEEAIRKAFQMLDKDKSGFIEWNEIKYILSTVPSSMpvapLSDEEAEAMIQAA----DTD 90

                         90
                 ....*....|....*
gi 392920728 144 GDGKISFQEFCDVVE 158
Cdd:cd16252   91 GDGRIDFQEFSDMVK 105

EF-hand, calcium binding motif, found in mitochondrial calcium uptake proteins MICU1, MICU2, MICU3, and similar proteins; This family includes mitochondrial calcium uptake protein MICU1 and its two additional paralogs, MICU2 and MICU3. MICU1 localizes to the inner mitochondrial membrane (IMM). It functions as a gatekeeper of the mitochondrial calcium uniporter (MCU) and regulates MCU-mediated mitochondrial Ca2+ uptake, which is essential for maintaining mitochondrial homoeostasis. MICU1 and MICU2 are physically associated within the uniporter complex and are co-expressed across all tissues. They may play non-redundant roles in the regulation of the mitochondrial calcium uniporter. At present, the precise molecular function of MICU2 and MICU3 remain unclear. MICU2 may play possible roles in Ca2+ sensing and regulation of MCU, calcium buffering with a secondary impact on transport or assembly and stabilization of MCU. MICU3 likely has a role in mitochondrial calcium handling. All members in this family contains an N-terminal mitochondrial targeting sequence (MTS) as well as two evolutionarily conserved canonical Ca2+-binding EF-hands separated by a long stretch of residues predicted to form alpha-helices.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920728  27 FKKLDVDGSGSLSVEEFMSLPEL--QQNPLVQRVIDI------------------FDEDGNGEV---DFREFIQGISQFS 83
Cdd:cd15900    6 FKMFDLDGDGELDKEEFNKVQSIirSQTSVGQRHRDHtngestklgmnstlaryfFGKDGKQKLsieKFLEFQENLQEEI 85

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 392920728  84 vkGDKNTKLKFaFRIYDMDrdgfISNGELFQVLKMMVGNNLKDsqlqQIVDKTILFHDKDGDGKISFQEFCDV 156
Cdd:cd15900   86 --DDVDTALTF-YHLAGAS----IDRKTFKRAAKVVAGVELSD----HVVDVVFTIFDEDGDGILSHKEFISV 147

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 392920728  16 DAYELRRLTRRFKKLDVDGSGSLSVEEFMSLPELQQNP-----LVQRVIDIFDEDGNGEVDFREFIQGISQFSV----KG 86
Cdd:cd16225  126 DKEVLDRYKDRWSQADEPEDGLLDVEEFLSFRHPEHSRgmlknMVKEILHDLDQDGDEKLTLDEFVSLPPGTVEeqqaED 205

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 392920728  87 DKNTK--LKFAFRI-YDMDRDGFISNGELFQVLKMMVGNNLKdSQLQQIvdktILFHDKDGDGKISFQE 152
Cdd:cd16225  206 DDEWKkeRKKEFEEvIDLNHDGKVTKEELEEYMDPRNERHAL-NEAKQL----IAVADENKDGKLSLEE 269

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 392920728  21 RRLTRRFKKLDVDGSGSLSVEEFMSLPELQQNPLVQRVIDI----FDEDGNGEVDFREFIQGISQFSVKGDKNTKLKFA- 95
Cdd:cd16226   35 ERLGIIVDKIDKNGDGFVTEEELKDWIKYVQKKYIREDVDRqwkeYDPNKDGKLSWEEYKKATYGFLDDEEEDDDLHESy 114

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 392920728  96 ----------FRIYDMDRDGFISNGELFQVLKMMVGNNLKDSqlqqIVDKTILFHDKDGDGKISFQEF 153
Cdd:cd16226  115 kkmirrderrWKAADQDGDGKLTKEEFTAFLHPEEFPHMRDI----VVQETLEDIDKNKDGFISLEEY 178

EF-hand, calcium binding motif, found in alpha-parvalbumin; Alpha-parvalbumin is cytosolic Ca2+/Mg2+-binding protein expressed mainly in fast-twitch skeletal myofibrils, where it may act as a soluble relaxing factor facilitating the Ca2+-mediated relaxation phase. It is also expressed in rapidly firing neurons, particularly GABA-ergic neurons, and thus may confer protection against Ca2+ toxicity. The major role of alpha-parvalbumin is metal buffering and transport of Ca2+. It binds different metal cations, and exhibits very high affinity for Ca2+ and physiologically significant affinity for Mg2+. Alpha-parvalbumin is 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+. Both metal ion-binding sites in alpha-parvalbumin are high-affinity sites. Additionally, in contrast to beta-parvalbumin, alpha-parvalbumin is less acidic and has an additional residue in the C-terminal helix.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920728  71 DFREFIQGISqfsVKGDKNTKLKFAFRIYDMDRDGFISNGELFQVLKMMV--GNNLKDSQLQQIVDKTilfhDKDGDGKI 148
Cdd:cd16254   18 DYKKFFEMVG---LKKKSADDVKKVFHILDKDKSGFIEEDELKFVLKGFSpdGRDLSDKETKALLAAG----DKDGDGKI 90

                 ....*....
gi 392920728 149 SFQEFCDVV 157
Cdd:cd16254   91 GIDEFATLV 99

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 392920728  68 GEVDFREFIQGISQFSVKGDKntkLKFAFRIYDMDRDGFISNGELFQVLKMM--VGNNLKDSQLQQIVDKTilfhDKDGD 145
Cdd:cd16251   15 GSFNYKKFFEHVGLKQKSEDQ---IKKVFQILDKDKSGFIEEEELKYILKGFsiAGRDLTDEETKALLAAG----DTDGD 87

                         90
                 ....*....|..
gi 392920728 146 GKISFQEFCDVV 157
Cdd:cd16251   88 GKIGVEEFATLV 99

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 392920728  20 LRRLTRRFKKLDVDGSGSLSVEEFMSL--PE---LQQNPLVQRVIDIFDEDGNGEVDFREFI 76
Cdd:cd16226  118 IRRDERRWKAADQDGDGKLTKEEFTAFlhPEefpHMRDIVVQETLEDIDKNKDGFISLEEYI 179

EF-hand, calcium binding motif, found in Drosophila melanogaster calbindin-32 (CBN) and similar proteins; CBN, the product of the cbn gene, is a Drosophila homolog to vertebrate neuronal six EF-hand calcium binding proteins. It is expressed through most of ontogenesis with a selective distribution in the nervous system and in a few small adult thoracic muscles. Its precise biological role remains unclear. CBN contains six EF-hand motifs, but some of them may not bind calcium ions due to the lack of key residues.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 392920728  95 AFRIYDMDRDGFISNGELFQVLKMMVGNNLKDSQLQQIVD--KTILFH-DKDGDGKISFQEFCDVV 157
Cdd:cd16179  193 VFALYDRDNNGTIENEELTGFLKDLLELVQEDYDEQDLEEfkEIILRGwDFNNDGKISRKELTMLL 258

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 392920728  23 LTRRFKKLDVDgSGSLSVEEFMSL--------PELQQNPLVQR-VIDIFDEDGNGEVDFREFiQGISQFSvkgdknTKLK 93
Cdd:cd15897    2 LRNVFQAVAGD-DGEISATELQQAlsnvgwthFDLGFSLETCRsMIAMMDRDHSGKLNFSEF-KGLWNYI------KAWQ 73

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920728  94 FAFRIYDMDRDGFISNGELFQVLKMMvGNNLKDSQLQQIVDKTilfhdKDGDGKISFQEF 153
Cdd:cd15897   74 EIFRTYDTDGSGTIDSNELRQALSGA-GYRLSEQTYDIIIRRY-----DRGRGNIDFDDF 127

centrin; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 392920728  87 DKNTKLKFAFRIYDMDRDGFISNGELFQVLKMMvGNNLKDSQLQQIvdktILFHDKDGDGKISFQEFCDVV 157
Cdd:PTZ00183  14 DQKKEIREAFDLFDTDGSGTIDPKELKVAMRSL-GFEPKKEEIKQM----IADVDKDGSGKIDFEEFLDIM 79

EF-hand, calcium binding motif, found in Drosophila melanogaster calbindin-32 (CBN) and similar proteins; CBN, the product of the cbn gene, is a Drosophila homolog to vertebrate neuronal six EF-hand calcium binding proteins. It is expressed through most of ontogenesis with a selective distribution in the nervous system and in a few small adult thoracic muscles. Its precise biological role remains unclear. CBN contains six EF-hand motifs, but some of them may not bind calcium ions due to the lack of key residues.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392920728  54 LVQRVIDIFDEDGNGEVDFREFIQGIS---------QFSVKGDKNTKLKFAFRIYDMDRDGFISNGELFQVLKMMVGN-- 122
Cdd:cd16179   50 LKEEFMEAYDENQDGRIDIRELAQLLPteenflllfRRDNPLDSSVEFMKVWREYDKDNSGYIEADELKNFLKHLLKEak 129

                         90       100       110
                 ....*....|....*....|....*....|...
gi 392920728 123 ---NLKDSQLQQIVDKTILFHDKDGDGKISFQE 152
Cdd:cd16179  130 rdnDVSEDKLIEYTDTILQLFDRNKDGKLQLSE 162

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 392920728    91 KLKFAFRIYDMDRDGFISNGELFQVLKMM 119
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

Penta-EF hand, calcium binding motifs, found in calpain-9 (CAPN9); CAPN9, also termed digestive tract-specific calpain, or new calpain 4 (nCL-4), or protein CG36, is a calpain large subunit predominantly expressed in gastrointestinal tract. It plays a physiological role in the suppression of tumorigenesis. It acts as an important biomolecule link for the regression of colorectal cancer via intracellular calcium homeostasis. CAPN9 may also play a critical role in lumen formation. Moreover, CAPN9, together with CAPN8, forms an active protease complex, G-calpain, in which both proteins are essential for stability and activity. The G-Calpain has been implicated in gastric mucosal defense. Furthermore, down-regulation of calpain 9 has been linked to hypertensive heart and kidney disease in salt-sensitive Dahl rats. CAPN9 contains 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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 392920728  58 VIDIFDEDGNGEVDFREFiqgisqfSVKGDKNTKLKFAFRIYDMDRDGFISNGELFQVLKmMVGNNLKDSQLQQIV 133
Cdd:cd16192   48 IISLMDTSGNGKLGFSEF-------KVFWDKLKKWIGLFLKYDADRSGTMSSYELRSALK-AAGFQLNNQLLQLIV 115