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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235516   3 RGELSRVFQMFDKNGDGKIAKNELKDFFksvgimvpENEINEMIAKMDVNGDGAMDIDEFGSlYQEMVEEKEEEEDMREA 82
Cdd:COG5126   4 RRKLDRRFDLLDADGDGVLERDDFEALF--------RRLWATLFSEADTDGDGRISREEFVA-GMESLFEATVEPFARAA 74

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 15235516  83 FRVFDQNGDGFITDEELRSVLASMGLkqgrTLEDCKKMISKVDVDGDGMVNFKEFKQMMRG 143
Cdd:COG5126  75 FDLLDTDGDGKISADEFRRLLTALGV----SEEEADELFARLDTDGDGKISFEEFVAAVRD 131

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 15235516    82 AFRVFDQNGDGFITDEELRSVLASMGLKQGRTLEDCKKMISKVDVDGDGMVNFKEFKQMMR 142
Cdd:pfam13499   7 AFKLLDSDGDGYLDVEELKKLLRKLEEGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235516   44 EMIAKMDVNGDGAMDIDEFGSLyQEMVEEKEEEEDMREAFRVFDQNGDGFITDEELRSVLA-----SMGLKQGRTLEDck 118
Cdd:NF041410  31 QLFAKLDSDGDGSVSQDELSSA-LSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAPpppppPDQAPSTELADD-- 107

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 15235516  119 kMISKVDVDGDGMVNFKEFKQMMRGGG--------FAALSSN 152
Cdd:NF041410 108 -LLSALDTDGDGSISSDELSAGLTSAGssadssqlFSALDSD 148

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235516    6 LSRVFQMFDKNGDGKIAKNELKDFFKS---VGIMVPENEI-NEMIAKMDVNGDGAMDIDEFGSLYQEMVEEKEEEEDmre 81
Cdd:NF041410  65 LSELFSDLDSDGDGSLSSDELAAAAPPpppPPDQAPSTELaDDLLSALDTDGDGSISSDELSAGLTSAGSSADSSQL--- 141

                         90       100       110
                 ....*....|....*....|....*....|...
gi 15235516   82 aFRVFDQNGDGFITDEELRSVLASMGLKQGRTL 114
Cdd:NF041410 142 -FSALDSDGDGSVSSDELAAALQPPPPPPLFSL 173

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235516   3 RGELSRVFQMFDKNGDGKIAKNELKDFFksvgimvpENEINEMIAKMDVNGDGAMDIDEFGSlYQEMVEEKEEEEDMREA 82
Cdd:COG5126   4 RRKLDRRFDLLDADGDGVLERDDFEALF--------RRLWATLFSEADTDGDGRISREEFVA-GMESLFEATVEPFARAA 74

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 15235516  83 FRVFDQNGDGFITDEELRSVLASMGLkqgrTLEDCKKMISKVDVDGDGMVNFKEFKQMMRG 143
Cdd:COG5126  75 FDLLDTDGDGKISADEFRRLLTALGV----SEEEADELFARLDTDGDGKISFEEFVAAVRD 131

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 15235516  82 AFRVFDQNGDGFITDEELRSVLASMGLKQgrTLEDCKKMISKVDVDGDGMVNFKEFKQMMR 142
Cdd:cd00051   5 AFRLFDKDGDGTISADELKAALKSLGEGL--SEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 15235516    82 AFRVFDQNGDGFITDEELRSVLASMGLKQGRTLEDCKKMISKVDVDGDGMVNFKEFKQMMR 142
Cdd:pfam13499   7 AFKLLDSDGDGYLDVEELKKLLRKLEEGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235516    8 RVFQMFDKNGDGKIAKNELKDFF--KSVGIMVpeNEINEMIAKMDVNGDGAMDIDEFGSLYQEMVEEKEEEEDMREA--- 82
Cdd:NF041410  31 QLFAKLDSDGDGSVSQDELSSALssKSDDGSL--IDLSELFSDLDSDGDGSLSSDELAAAAPPPPPPPDQAPSTELAddl 108

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235516   83 FRVFDQNGDGFITDEELRSVLASMGlkqgrTLEDCKKMISKVDVDGDGMVNFKEFKQMMR 142
Cdd:NF041410 109 LSALDTDGDGSISSDELSAGLTSAG-----SSADSSQLFSALDSDGDGSVSSDELAAALQ 163

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235516  37 VPENEINEMIAKMDVNGDGAMDIDEFGSLYqemveekeeEEDMREAFRVFDQNGDGFITDEELRSVLASMGLKQGRtlED 116
Cdd:COG5126   2 LQRRKLDRRFDLLDADGDGVLERDDFEALF---------RRLWATLFSEADTDGDGRISREEFVAGMESLFEATVE--PF 70

                        90       100       110
                ....*....|....*....|....*....|
gi 15235516 117 CKKMISKVDVDGDGMVNFKEFKQMMRGGGF 146
Cdd:COG5126  71 ARAAFDLLDTDGDGKISADEFRRLLTALGV 100

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 15235516   5 ELSRVFQMFDKNGDGKIAKNELKDFFkSVGIMVPENE--INEMIAKMDVNGDGAMDIDEFGSLYQemveekeEEEDMREA 82
Cdd:cd16183   1 FLWNVFQRVDKDRSGQISATELQQAL-SNGTWTPFNPetVRLMIGMFDRDNSGTINFQEFAALWK-------YITDWQNC 72

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 15235516  83 FRVFDQNGDGFITDEELRSVLASMGLKqgrtLED--CKKMISKVDVDGDGMVNFKEFKQ 139
Cdd:cd16183  73 FRSFDRDNSGNIDKNELKQALTSFGYR----LSDqfYDILVRKFDRQGRGTIAFDDFIQ 127

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 15235516   5 ELSRVFQMFDKNGDGKIAKNELKDFFKSVGIMVPENEINEMIAKMDVNGDGAMDIDEFGSLYQEMVEEKEeeedmreAFR 84
Cdd:cd16185   1 ELRQWFRAVDRDRSGSIDVNELQKALAGGGLLFSLATAEKLIRMFDRDGNGTIDFEEFAALHQFLSNMQN-------GFE 73

                        90       100
                ....*....|....*....|...
gi 15235516  85 VFDQNGDGFITDEELRSVLASMG 107
Cdd:cd16185  74 QRDTSRSGRLDANEVHEALAASG 96

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 15235516   5 ELSRVFQMFDKNGDGKIAKNELKDFFKSV----GIMVPEN----EINEMIAKMDVNGDGAMDIDEFGSL----------Y 66
Cdd:cd15902  91 EFMKIWRKYDTDGSGFIEAKELKGFLKDLllknKKHVSPPkldeYTKLILKEFDANKDGKLELDEMAKLlpvqenfllkF 170

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 15235516  67 QEMVEEKEEEEDMREAFRVFDQNGDGFITDEELRSVLASMGLKQ-----GRTLEDCKKMISKV-DVDGDGMVNFKEFK 138
Cdd:cd15902 171 QILGAMDLTKEDFEKVFEHYDKDNNGVIEGNELDALLKDLLEKNkadidKPDLENFRDAILRAcDKNKDGKIQKTELA 248

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 15235516   6 LSRVFQMFDKNGDGKIAKNELKDFFKSVGIMVPENEINEMIAKMDVNGDGAMDIDEFGSLYQEMVEEKEEEEDMREA--- 82
Cdd:cd16226  37 LGIIVDKIDKNGDGFVTEEELKDWIKYVQKKYIREDVDRQWKEYDPNKDGKLSWEEYKKATYGFLDDEEEDDDLHESykk 116

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 15235516  83 --------FRVFDQNGDGFITDEELRSVLASmglkqgrtlEDCKKM--------ISKVDVDGDGMVNFKEF 137
Cdd:cd16226 117 mirrderrWKAADQDGDGKLTKEEFTAFLHP---------EEFPHMrdivvqetLEDIDKNKDGFISLEEY 178

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 15235516   6 LSRVFQMFDKNGDGKIAKNELKDFFKSVGIMVPENEINEMIAKMDVNGDGAMDIDEFGSLYQemveEKEEEEDMREAFRV 85
Cdd:cd16202   2 LKDQFRKADKNGDGKLSFKECKKLLKKLNVKVDKDYAKKLFQEADTSGEDVLDEEEFVQFYN----RLTKRPEIEELFKK 77

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235516  86 FDQNGDgFITDEELRSVLASMGLKQGRTLEDCKKMISKVDVDGD----GMVNFKEFKQMM 141
Cdd:cd16202  78 YSGDDE-ALTVEELRRFLQEEQKVKDVTLEWAEQLIETYEPSEDlkaqGLMSLDGFTLFL 136

centrin; Provisional

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235516    3 RGELSRVFQMFDKNGDGKIAKNELKDFFKSVGIMVPENEINEMIAKMDVNGDGAMDIDEF 62
Cdd:PTZ00183  89 REEILKAFRLFDDDKTGKISLKNLKRVAKELGETITDEELQEMIDEADRNGDGEISEEEF 148

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 15235516  14 DKNGDGKIAKNELKDFF---KSVGIMvpENEINEMIAKMDVNGDGAMDIDEFGSL------YQEMVEEKEEEEDMREAFR 84
Cdd:cd16225 141 DEPEDGLLDVEEFLSFRhpeHSRGML--KNMVKEILHDLDQDGDEKLTLDEFVSLppgtveEQQAEDDDEWKKERKKEFE 218

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|...
gi 15235516  85 -VFDQNGDGFITDEELRSVLASMGLKQgrTLEDCKKMISKVDVDGDGMVNFKE 136
Cdd:cd16225 219 eVIDLNHDGKVTKEELEEYMDPRNERH--ALNEAKQLIAVADENKDGKLSLEE 269

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 15235516   5 ELSRVFQMFDKNGDGKIAKNELKDFFKSVGIMVP---ENEINEMIAKMDVNGDGAMDIDEFGSLYQ 67
Cdd:cd16251  35 QIKKVFQILDKDKSGFIEEEELKYILKGFSIAGRdltDEETKALLAAGDTDGDGKIGVEEFATLVA 100

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 15235516   6 LSRVFQMFDKNGDGKIAKNELKDFFKSVGIMVPENEINEMIAKMDVNGD-------------GAMDIDEFGSLYQEMVEE 72
Cdd:cd16227  38 LAVLAKKMDLNDDGFIDRKELKAWILRSFKMLDEEEANERFEEADEDGDgkvtweeyladsfGYDDEDNEEMIKDSTEDD 117

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 15235516  73 KEEEEDMREAFRVFDQNGDGFITDEELRSVLASMGLKQGRTLEDCKKMISKvDVDGDGMVNFKEF 137
Cdd:cd16227 118 LKLLEDDKEMFEAADLNKDGKLDKTEFSAFQHPEEYPHMHPVLIEQTLRDK-DKDNDGFISFQEF 181

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
                ....*....|....*....|....*....|....*....|....*....|....
gi 15235516  90 GDGFITDEELRSVLASMGLK---QGRTLEDCKKMISKVDVDGDGMVNFKEFKQM 140
Cdd:cd15897  12 DDGEISATELQQALSNVGWThfdLGFSLETCRSMIAMMDRDHSGKLNFSEFKGL 65

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 15235516   6 LSRVFQMFDKNGDGKIAKNELKDFFKSVGIMVP-----ENEINEMIAKMDVNGDGAMDIDEFGSLYQ 67
Cdd:cd16252  39 IRKAFQMLDKDKSGFIEWNEIKYILSTVPSSMPvaplsDEEAEAMIQAADTDGDGRIDFQEFSDMVK 105

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 15235516  82 AFRVFDQNGDGFITDEELRSVLASMGLkQGRTL--EDCKKMISKVDVDGDGMVNFKEFKQMMRG 143
Cdd:cd16251  39 VFQILDKDKSGFIEEEELKYILKGFSI-AGRDLtdEETKALLAAGDTDGDGKIGVEEFATLVAG 101

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

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 15235516      9 VFQMFDKNGDGKIAKNELKDFFKSVGImvPENEINEMIAKMDVNGDGAMDIDEF 62
Cdd:smart00027  15 IFRSLDKNQDGTVTGAQAKPILLKSGL--PQTLLAKIWNLADIDNDGELDKDEF 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 15235516   7 SRVFQMFDKNGDGKIAKNELKDFFKSVGIMVPENEINEMIAKMDVNGDGAMDIDEFgslyqemVEEKEEEEDMREAFRVF 86
Cdd:cd16180  70 RRLFRRFDRDRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDF-------VEACVTLKRLTDAFRKY 142

                ....*....
gi 15235516  87 DQNGDGFIT 95
Cdd:cd16180 143 DTNRTGYAT 151

Penta-EF hand, calcium binding motifs, found in sorcin; 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. The up-regulation of sorcin is correlated with a number of cancer types, including colorectal, gastric and breast cancer. It may represent a therapeutic target for reversing tumor multidrug resistance (MDR). Sorcin participates in the regulation of calcium homeostasis in cells and is necessary for the activation of mitosis and cytokinesis. It enhances metastasis and promotes epithelial-to-mesenchymal transition of colorectal cancer. Moreover, sorcin has been implicated in the regulation of intracellular Ca2+ cycling and cardiac excitation-contraction coupling. It displays the anti-apoptotic properties via the modulation of mitochondrial Ca2+ handling in cardiac myocytes. It can target and activate the sarcolemmal Na+/Ca2+ exchanger (NCX1) in cardiac muscle. Meanwhile, sorcin modulates cardiac L-type Ca2+ current by functional interaction with the alpha1C subunit. It also associates with calcium/calmodulin-dependent protein kinase IIdeltaC (CaMKIIdelta(C)) and further modulates ryanodine receptor (RyR) function in cardiac myocytes. Furthermore, sorcin may act as a Ca2+ sensor for glucose-induced nuclear translocation and the activation of carbohydrate-responsive element-binding protein (ChREBP)-dependent genes. As a mitochondrial chaperone TRAP1 interactor, sorcin involves in mitochondrial metabolism through the TRAP1 pathway. In addition, sorcin may regulate the inhibition of type I interferon response in cells through interacting with foot-and-mouth disease virus (FMDV) VP1. Sorcin 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.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|...
gi 15235516  91 DGFITDEELRSVLASMGLKQGR---TLEDCKKMISKVDVDGDGMVNFKEFKQM 140
Cdd:cd16187  13 DGQIDADELQRCLTQSGIAGGYkpfNLETCRLMISMLDRDMSGTMGFNEFKEL 65

EF-hand, calcium binding motif, found in beta-parvalbumin; Beta-parvalbumin, also termed Oncomodulin-1 (OM), is a small calcium-binding protein that is expressed in hepatomas, as well as in the blastocyst and the cytotrophoblasts of the placenta. It is also found to be expressed in the cochlear outer hair cells of the organ of Corti and frequently expressed in neoplasms. Mammalian beta-parvalbumin is secreted by activated macrophages and neutrophils. It may function as a tissue-specific Ca2+-dependent regulatory protein, and may also serve as a specialized cytosolic Ca2+ buffer. Beta-parvalbumin acts as a potent growth-promoting signal between the innate immune system and neurons in vivo. It has high and specific affinity for its receptor on retinal ganglion cells (RGC) and functions as the principal mediator of optic nerve regeneration. It exerts its effects in a cyclic adenosine monophosphate (cAMP)-dependent manner and can further elevate intracellular cAMP levels. Moreover, beta-parvalbumin is associated with efferent function and outer hair cell electromotility, and can identify different hair cell types in the mammalian inner ear. Beta-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+. The EF site displays a high-affinity for Ca2+/Mg2+, and the CD site is a low-affinity Ca2+-specific site. In addition, beta-parvalbumin is distinguished from other parvalbumins by its unusually low isoelectric point (pI = 3.1) and sequence eccentricities (e.g., Y57-L58-D59 instead of F57-I58-E59).

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 15235516  82 AFRVFDQNGDGFITDEELRSVLASMGlKQGRTLEDC--KKMISKVDVDGDGMVNFKEFKQM 140
Cdd:cd16255  39 VFEIIDQDKSGFIEEEELKLFLQNFS-SGARELTDAetKAFLKAGDSDGDGKIGVEEFQAL 98

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 15235516   116 DCKKMISKVDVDGDGMVNFKEFKQMMR 142
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLK 27

Penta-EF hand, calcium binding motifs, found in grancalcin; Grancalcin (GCA) is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It displays a Ca2+-dependent translocation to granules and plasma membrane upon neutrophil activation, suggesting roles in granule-membrane fusion and degranulation of neutrophils. It may also play a role in the regulation of vesicle/granule exocytosis through the reversible binding of secretory vesicles and plasma membranes upon the presence of calcium. Moreover, GCA is involved in inflammation, as well as in the process of adhesion of neutrophils to fibronectin. It plays a key role in leukocyte-specific functions that are responsible for host defense, and affects the function of integrin receptors on immune cells through binding to L-plastin in the absence of calcium. Furthermore, GCA 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. GCA binds two Ca2+ ions through its EF1 and EF3 hands.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 15235516  91 DGFITDEELRSVLASMGLKQGRT---LEDCKKMISKVDVDGDGMVNFKEFKQMmrgggFAALSS 151
Cdd:cd16186  13 DGEVDAEELQRCLTQSGINGTYTpfsLETCRIMIAMLDRDHTGKMGFNEFKEL-----WAALNA 71

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 15235516   8 RVFQMFDKNGDGKIAKNELKDFFKSVGIMVPENEINEMIAKMDVNGDGAMDIDEF-------GSLyqemveekeeeedmR 80
Cdd:cd16183  71 NCFRSFDRDNSGNIDKNELKQALTSFGYRLSDQFYDILVRKFDRQGRGTIAFDDFiqccvvlQTL--------------T 136

                        90
                ....*....|....*
gi 15235516  81 EAFRVFDQNGDGFIT 95
Cdd:cd16183 137 DSFRRYDTDQDGWIQ 151

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 15235516    118 KKMISKVDVDGDGMVNFKEFKQMMR 142
Cdd:smart00054   3 KEAFRLFDKDGDGKIDFEEFKDLLK 27

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 15235516  84 RVFDQ--NGDGFITDEELRSVLAS-----MGLKQGRTLEDCKKMISKVDVDGDGMVNFKEFKQMM 141
Cdd:cd16182   4 ELFEKlaGEDEEIDAVELQKLLNAsllkdMPKFDGFSLETCRSLIALMDTNGSGRLDLEEFKTLW 68

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 15235516   3 RGELSRVFQMFDKNGDGKIAKNELKDFFKSVGIMVPENEINEMIAKMDVNGDGAMDIDEF-----GSLYQEMVEEKEEEE 77
Cdd:cd15899  34 KRRLGVIVSKMDVDKDGFISAKELHSWILESFKRHAMEESKEQFRAVDPDEDGHVSWDEYkndtyGSVGDDEENVADNIK 113

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15235516  78 DMR----------EAFRVFDQNGDGFITDEELRSVL---ASMGLKQ---GRTLEDckkmiskVDVDGDGMVNFKEFKQMM 141
Cdd:cd15899 114 EDEeykklllkdkKRFEAADQDGDLILTLEEFLAFLhpeESPYMLDfviKETLED-------LDKNGDGFISLEEFISDP 186

                ..
gi 15235516 142 RG 143
Cdd:cd15899 187 YS 188

Penta-EF hand, calcium binding motifs, found in calpain-13 (CAPN13), calpain-14 (CAPN14), and similar proteins; CAPN13, also termed calcium-activated neutral proteinase 13 (CANP 13), a 63.6 kDa calpain large subunit that exhibits a restricted tissue distribution with low levels of expression detected only in human testis and lung. In calpain family, CAPN13 is most closely related to calpain-14 (CAPN14). CAPN14, also termed calcium-activated neutral proteinase 14 (CANP 14), is a 76.7 kDa calpain large subunit that is most highly expressed in the oesophagus. Its expression and calpain activity can be induced by IL-13. Both CAPN13 and CAPN14 contain 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 15235516  45 MIAKMDVNGDGAMDIDEFGSLYQEMVEEKEEeedmreaFRVFDQNGDGFITDEELRSVLASMGLK 109
Cdd:cd16195  48 MVALMDLSVNGRLSLEEFSRLWKKLRKYKDI-------FQKADVSKSGFLSLSELRNAIQAAGIR 105

EF-hand domain;