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 4506335    9 AEDIKKAVGAFSATDSFDHKKFFQMVGLKKKSADDVKKVFHMLDKDKSGFIEEDELGFILKGFSPDARDLSAKETKMLMA 88
Cdd:cd16254   1 AEDIKKAVGAFAAADSFDYKKFFEMVGLKKKSADDVKKVFHILDKDKSGFIEEDELKFVLKGFSPDGRDLSDKETKALLA 80

                        90       100
                ....*....|....*....|.
gi 4506335   89 AGDKDGDGKIGVDEFSTLVAE 109
Cdd:cd16254  81 AGDKDGDGKIGIDEFATLVAE 101

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 4506335    9 AEDIKKAVGAFSATDSFDHKKFFQMVGLKKKSADDVKKVFHMLDKDKSGFIEEDELGFILKGFSPDARDLSAKETKMLMA 88
Cdd:cd16254   1 AEDIKKAVGAFAAADSFDYKKFFEMVGLKKKSADDVKKVFHILDKDKSGFIEEDELKFVLKGFSPDGRDLSDKETKALLA 80

                        90       100
                ....*....|....*....|.
gi 4506335   89 AGDKDGDGKIGVDEFSTLVAE 109
Cdd:cd16254  81 AGDKDGDGKIGIDEFATLVAE 101

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

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 4506335   41 ADDVKKVFHMLDKDKSGFIEEDELGFILKGFspdarDLSAKETKMLMAAGDKDGDGKIGVDEFSTLVAE 109
Cdd:COG5126  68 EPFARAAFDLLDTDGDGKISADEFRRLLTAL-----GVSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

centrin; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 4506335    28 KKFFQMVGLKKKSADDVKKVFHMLDKDKSGFIEEDELGFILK--GFSPdardlSAKETKMLMAAGDKDGDGKIGVDEF 103
Cdd:PTZ00183   3 KRRSERPGLTEDQKKEIREAFDLFDTDGSGTIDPKELKVAMRslGFEP-----KKEEIKQMIADVDKDGSGKIDFEEF 75

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 4506335    9 AEDIKKAVGAFSATDSFDHKKFFQMVGLKKKSADDVKKVFHMLDKDKSGFIEEDELGFILKGFSPDARDLSAKETKMLMA 88
Cdd:cd16254   1 AEDIKKAVGAFAAADSFDYKKFFEMVGLKKKSADDVKKVFHILDKDKSGFIEEDELKFVLKGFSPDGRDLSDKETKALLA 80

                        90       100
                ....*....|....*....|.
gi 4506335   89 AGDKDGDGKIGVDEFSTLVAE 109
Cdd:cd16254  81 AGDKDGDGKIGIDEFATLVAE 101

EF-hand, calcium binding motif, found in parvalbumins; 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 4506335    9 AEDIKKAVGAFSATDSFDHKKFFQMVGLKKKSADDVKKVFHMLDKDKSGFIEEDELGFILKGFSPDARDLSAKETKMLMA 88
Cdd:cd16253   1 ANDIDIALAACQAADSFDHKAFFKAVGLSKKSPADIKKVFNILDQDKSGFIEEEELKLFLKNFSDGARVLSDKETKNFLA 80

                        90       100
                ....*....|....*....|.
gi 4506335   89 AGDKDGDGKIGVDEFSTLVAE 109
Cdd:cd16253  81 AGDSDGDGKIGVDEFKSMVKA 101

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 4506335   24 SFDHKKFFQMVGLKKKSA---DDVKKVFHMLDKDKSGFIEEDELGFILKGF--SPDARDLSAKETKMLMAAGDKDGDGKI 98
Cdd:cd16252  16 SFNYSKFFEYMQKFQTSEqqeEAIRKAFQMLDKDKSGFIEWNEIKYILSTVpsSMPVAPLSDEEAEAMIQAADTDGDGRI 95

                        90
                ....*....|.
gi 4506335   99 GVDEFSTLVAE 109
Cdd:cd16252  96 DFQEFSDMVKK 106

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 4506335     42 DDVKKVFHMLDKDKSGFIEEDELGFILKGFSPDArDLSAKETKMLMAAGDKDGDGKIGVDEFSTLV 107
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGE-PLSDEEVEELFKEFDLDKDGRISFEEFLELY 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 4506335   43 DVKKVFHMLDKDKSGFIEEDELGFILKGFSPDARDLSAkeTKMLMAAGDKDGDGKIGVDEFSTL 106
Cdd:cd16180   1 ELRRIFQAVDRDRSGRISAKELQRALSNGDWTPFSIET--VRLMINMFDRDRSGTINFDEFVGL 62

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 4506335   35 GLKKKSADDVKKVFHMLDKDKSGFIEEDElgfiLKGFSPDARDLSAKE---------TKMLMAAGDKDGDGKIGVDEFST 105
Cdd:cd16179 181 GAGKLTREDIDRVFALYDRDNNGTIENEE----LTGFLKDLLELVQEDydeqdleefKEIILRGWDFNNDGKISRKELTM 256

                ..
gi 4506335  106 LV 107
Cdd:cd16179 257 LL 258

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 4506335   31 FQMVGLKKKSADDVKKVFHMLDKDKSGFIEEDELGFILKGF------SPDARDLSAKEtKMLMAAGDKDGDGKIGVDE 102
Cdd:cd15902 170 FQILGAMDLTKEDFEKVFEHYDKDNNGVIEGNELDALLKDLleknkaDIDKPDLENFR-DAILRACDKNKDGKIQKTE 246

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 4506335   47 VFHMLDKDKSGFIEEDELGFIL-----KGFSPdardlsakET-KMLMAAGDKDGDGKIGVDEFSTL 106
Cdd:cd16183   5 VFQRVDKDRSGQISATELQQALsngtwTPFNP--------ETvRLMIGMFDRDNSGTINFQEFAAL 62

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 4506335   37 KKKSADDVKKVFHMLDKDKSGFIEEDEL-GF----ILKGFSPDARDLSAKETKMLMAAGDKDGDGKIGVDEFSTL 106
Cdd:cd15902  85 PLISSVEFMKIWRKYDTDGSGFIEAKELkGFlkdlLLKNKKHVSPPKLDEYTKLILKEFDANKDGKLELDEMAKL 159

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

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 4506335   41 ADDVKKVFHMLDKDKSGFIEEDELGFILKGFspdardlsakeTKMLMAAGDKDGDGKIGVDEFSTLVA 108
Cdd:COG5126   4 RRKLDRRFDLLDADGDGVLERDDFEALFRRL-----------WATLFSEADTDGDGRISREEFVAGME 60

phosphatidylserine decarboxylase

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 4506335    44 VKKVFHMLDKDKSGFIEEDELGFILKGFspdARDLSAKETKMLMAAGDKDGDGKIGVDEFSTLVA 108
Cdd:PLN02964 181 ARRILAIVDYDEDGQLSFSEFSDLIKAF---GNLVAANKKEELFKAADLNGDGVVTIDELAALLA 242

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

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 4506335   43 DVKKVFHMLDKDKSGFIEEDELgfiLKGFSPDARDLSAKETKMLMAAGDKDGDGKIGVDEFSTLVAE 109
Cdd:COG5126  34 LWATLFSEADTDGDGRISREEF---VAGMESLFEATVEPFARAAFDLLDTDGDGKISADEFRRLLTA 97