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 226533801   9 AEDIKKAVGAFSAAESFNYKKFFEMVGLKKKSPEDVKKVFHILDKDRSGFIEEEELKFVLKGFTPDGRDLSDKETKALLA 88
Cdd:cd16254    1 AEDIKKAVGAFAAADSFDYKKFFEMVGLKKKSADDVKKVFHILDKDKSGFIEEDELKFVLKGFSPDGRDLSDKETKALLA 80

                         90       100
                 ....*....|....*....|.
gi 226533801  89 AGDKDGDGKIGADEFATMVAE 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 226533801   9 AEDIKKAVGAFSAAESFNYKKFFEMVGLKKKSPEDVKKVFHILDKDRSGFIEEEELKFVLKGFTPDGRDLSDKETKALLA 88
Cdd:cd16254    1 AEDIKKAVGAFAAADSFDYKKFFEMVGLKKKSADDVKKVFHILDKDKSGFIEEDELKFVLKGFSPDGRDLSDKETKALLA 80

                         90       100
                 ....*....|....*....|.
gi 226533801  89 AGDKDGDGKIGADEFATMVAE 109
Cdd:cd16254   81 AGDKDGDGKIGIDEFATLVAE 101

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

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 226533801  42 EDVKKVFHILDKDRSGFIEEEELKFVLKGFtpdgrDLSDKETKALLAAGDKDGDGKIGADEFATMVAE 109
Cdd:COG5126   69 PFARAAFDLLDTDGDGKISADEFRRLLTAL-----GVSEEEADELFARLDTDGDGKISFEEFVAAVRD 131

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 226533801  43 DVKKVFHILDKDRSGFIEEEELKFVLKGFTPDGRDLSDKET-KALLAAGDKDGDGKIGADEFAT 105
Cdd:NF041410  64 DLSELFSDLDSDGDGSLSSDELAAAAPPPPPPPDQAPSTELaDDLLSALDTDGDGSISSDELSA 127

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 226533801  51 LDKDRSGFIEEEELKfvlKGFTPDGrdlSDKETKALLAAGDKDGDGKIGADEFA 104
Cdd:NF041410 112 LDTDGDGSISSDELS---AGLTSAG---SSADSSQLFSALDSDGDGSVSSDELA 159

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 226533801   9 AEDIKKAVGAFSAAESFNYKKFFEMVGLKKKSPEDVKKVFHILDKDRSGFIEEEELKFVLKGFTPDGRDLSDKETKALLA 88
Cdd:cd16254    1 AEDIKKAVGAFAAADSFDYKKFFEMVGLKKKSADDVKKVFHILDKDKSGFIEEDELKFVLKGFSPDGRDLSDKETKALLA 80

                         90       100
                 ....*....|....*....|.
gi 226533801  89 AGDKDGDGKIGADEFATMVAE 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 226533801   9 AEDIKKAVGAFSAAESFNYKKFFEMVGLKKKSPEDVKKVFHILDKDRSGFIEEEELKFVLKGFTPDGRDLSDKETKALLA 88
Cdd:cd16253    1 ANDIDIALAACQAADSFDHKAFFKAVGLSKKSPADIKKVFNILDQDKSGFIEEEELKLFLKNFSDGARVLSDKETKNFLA 80

                         90       100
                 ....*....|....*....|.
gi 226533801  89 AGDKDGDGKIGADEFATMVAE 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 226533801  24 SFNYKKFFEMVGLKKKS---PEDVKKVFHILDKDRSGFIEEEELKFVLKGFTPDG--RDLSDKETKALLAAGDKDGDGKI 98
Cdd:cd16252   16 SFNYSKFFEYMQKFQTSeqqEEAIRKAFQMLDKDKSGFIEWNEIKYILSTVPSSMpvAPLSDEEAEAMIQAADTDGDGRI 95

                         90
                 ....*....|.
gi 226533801  99 GADEFATMVAE 109
Cdd:cd16252   96 DFQEFSDMVKK 106

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 226533801   42 EDVKKVFHILDKDRSGFIEEEELKFVLKGFTPdGRDLSDKETKALLAAGDKDGDGKIGADEFATMV 107
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKLEE-GEPLSDEEVEELFKEFDLDKDGRISFEEFLELY 66

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 226533801  24 SFNYKKFFEMVGLKKK---SPEDVKKVFHILDKDRSGFIEEEELKFVLkgfTPDGRDLSDKETKALLAAGDKDGDGKIGA 100
Cdd:PTZ00184  63 TIDFPEFLTLMARKMKdtdSEEEIKEAFKVFDRDGNGFISAAELRHVM---TNLGEKLTDEEVDEMIREADVDGDGQINY 139

                 ....*..
gi 226533801 101 DEFATMV 107
Cdd:PTZ00184 140 EEFVKMM 146

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 226533801  43 DVKKVFHILDKDRSGFIEEEELKFVLKGFtpDGRDLSDKETKALLAAGDKDGDGKIGADEFA 104
Cdd:cd16180    1 ELRRIFQAVDRDRSGRISAKELQRALSNG--DWTPFSIETVRLMINMFDRDRSGTINFDEFV 60

centrin; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 226533801  28 KKFFEMVGLKKKSPEDVKKVFHILDKDRSGFIEEEELKFVLKGFtpdGRDLSDKETKALLAAGDKDGDGKIGADEF 103
Cdd:PTZ00183   3 KRRSERPGLTEDQKKEIREAFDLFDTDGSGTIDPKELKVAMRSL---GFEPKKEEIKQMIADVDKDGSGKIDFEEF 75

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 226533801  45 KKVFHILDKDRSGFIEEEELKFVLKGfTPDGRDLSDkeTKALLAAGDKDGDGKIGADEFATM 106
Cdd:NF041410  30 KQLFAKLDSDGDGSVSQDELSSALSS-KSDDGSLID--LSELFSDLDSDGDGSLSSDELAAA 88

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 226533801  26 NYKKFFEMVGLKKKSPEDVKKVFHILDKDRSGFIEEEELKFVLKGF------TPDGRDLSDKEtKALLAAGDKDGDGKIG 99
Cdd:cd15902  165 NFLLKFQILGAMDLTKEDFEKVFEHYDKDNNGVIEGNELDALLKDLleknkaDIDKPDLENFR-DAILRACDKNKDGKIQ 243

                 ....*
gi 226533801 100 ADEFA 104
Cdd:cd15902  244 KTELA 248

centrin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 226533801  23 ESFNYKKFFEMVGLK---KKSPEDVKKVFHILDKDRSGFIEEEELKFVLKGFtpdGRDLSDKETKALLAAGDKDGDGKIG 99
Cdd:PTZ00183  68 GKIDFEEFLDIMTKKlgeRDPREEILKAFRLFDDDKTGKISLKNLKRVAKEL---GETITDEELQEMIDEADRNGDGEIS 144

                 ....
gi 226533801 100 ADEF 103
Cdd:PTZ00183 145 EEEF 148

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
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 226533801  48 FHILDKDRSGFIEEEELKFVLKGftpDGRDLSDKETKALLAAGDKDGDGKIGADEFATM 106
Cdd:cd16185    6 FRAVDRDRSGSIDVNELQKALAG---GGLLFSLATAEKLIRMFDRDGNGTIDFEEFAAL 61

EF-hand motif found in eukaryotic phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11) isozymes; PI-PLC isozymes are signaling enzymes that hydrolyze the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. This family corresponds to the four EF-hand motifs containing PI-PLC isozymes, including PI-PLC-beta (1-4), -gamma (1-2), -delta (1,3,4), -epsilon (1), -zeta (1), eta (1-2). Lower eukaryotes such as yeast and slime molds contain only delta-type isozymes. In contrast, other types of isoforms present in higher eukaryotes. This family also includes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase 1 (PLC1) from fungi. Some homologs from plants contain only two atypical EF-hand motifs and they are not included. All PI-PLC isozymes except sperm-specific PI-PLC-zeta share a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C2 domain. PI-PLC-zeta lacks the PH domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Most of EF-hand motifs found in PI-PLCs consist of a helix-loop-helix structure, but lack residues critical to metal binding. Moreover, the EF-hand region of most of PI-PLCs may have an important regulatory function, but it has yet to be identified. However, PI-PLC-zeta is a key exception. It is responsible for Ca2+ oscillations in fertilized oocytes and exhibits a high sensitivity to Ca2+ mediated through its EF-hand domain. In addition, PI-PLC-eta2 shows a canonical EF-loop directing Ca2+-sensitivity and thus can amplify transient Ca2+ signals. Also it appears that PI-PLC-delta1 can regulate the binding of PH domain to PIP2 in a Ca2+-dependent manner through its functionally important EF-hand domains. PI-PLCs can be activated by a variety of extracellular ligands, such as growth factors, hormones, cytokines and lipids. Their activation has been implicated in tumorigenesis and/or metastasis linked to migration, proliferation, growth, inflammation, angiogenesis and actin cytoskeleton reorganization. PI-PLC-beta isozymes are activated by G-protein coupled receptor (GPCR) through different mechanisms. However, PI-PLC-gamma isozymes are activated by receptor tyrosine kinase (RTK), such as Rho and Ras GTPases. In contrast, PI-PLC-epsilon are activated by both GPCR and RTK. PI-PLC-delta1 and PLC-eta 1 are activated by GPCR-mediated calcium mobilization. The activation mechanism for PI-PLC-zeta remains unclear.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 226533801  44 VKKVFHILDKDRSGFIEEEELKFVLKGFTPDgrdLSDKETKALLAAGDKDGDGKIGADEFATM 106
Cdd:cd15898    2 LRRQWIKADKDGDGKLSLKEIKKLLKRLNIR---VSEKELKKLFKEVDTNGDGTLTFDEFEEL 61

EF-hand, calcium binding motif, found in secretagogin (SCGN); SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a calcium sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. It also serves as a calcium buffer in neurons. Thus, SCGN may be linked to the pathogenesis of neurological diseases such as Alzheimer's, and also acts as a serum marker of neuronal damage, or as a tumor biomarker. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. All six EF hand motifs of SCGN in some eukaryotes, including D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, could potentially bind six calcium ions. In contrast, SCGNs from higher eukaryotes have at least one non-functional EF-hand motif due to the mutation(s) or deletions. For instance, the EF1 loop does not coordinate calcium ion due to the key residue asparagine replaced by lysine in SCGNs of many mammalian species. Moreover, the EF2 loop seems to be competent for calcium-binding in most mammalian SCGNs except for human and chimpanzee orthologs.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 226533801  52 DKDRSGFIEEEELK-FVLKGFTPDGRDLSDKE----TKALLAAGDKDGDGKIGADEFATMVA 108
Cdd:cd16178  102 DADSSGYISAAELKnFLRDLFLQHKKVITEDKldeyTDTMMKIFDKNKDGRLDLNDMARILA 163

EF-hand, calcium binding motif, found in calbindin (CB); CB, also termed calbindin D28, or D-28K, or avian-type vitamin D-dependent calcium-binding protein, is a unique intracellular calcium binding protein that functions as both a calcium sensor and buffer in eukaryotic cells, which undergoes a conformational change upon calcium binding and protects cells against insults of high intracellular calcium concentration. CB is highly expressed in brain and sensory neurons. It plays essential roles in neural functioning, altering synaptic interactions in the hippocampus, modulating calcium channel activity, calcium transients, and intrinsic neuronal firing activity. It prevents a neuronal death, as well as maintains and controls calcium homeostasis. CB also modulates the activity of proteins participating in the development of neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, and bipolar disorder. Moreover, CB interacts with Ran-binding protein M, a protein known to involve in microtubule function. It also interacts with alkaline phosphatase and myo-inositol monophosphatase, as well as caspase 3, an enzyme that plays an important role in the regulation of apoptosis. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions with high affinity.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 226533801  39 KSPEDVKKVFHILDKDRSGFIEEEELKFVLKGFTPDGRDLSDKE-----TKALLAAGDKDGDGKIGADEFATMV 107
Cdd:cd16176   82 KSSEEFMQTWRKYDADHSGFIEADELKSFLKDLLKKANKPFDESkleeyTHTMLKMFDSNNDGKLGLTEMARLL 155

Penta-EF hand, calcium binding motifs, found in sorcin, grancalcin, and similar proteins; The family corresponds to the second group of penta-EF hand (PEF) proteins that includes sorcin, grancalcin, and similar proteins. Sorcin, also termed 22 kDa Ca2+-binding protein, CP-22, or V19, is a soluble resistance-related calcium-binding protein that is expressed in normal mammalian tissues, such as the liver, lungs and heart. It contains a flexible glycine and proline-rich N-terminal extension and five EF-hand motifs that associate with membranes in a calcium-dependent manner. It may harbor three potential Ca2+ binding sites through its EF1, EF2 and EF3 hands. However, binding of only two Ca2+/monomer suffices to trigger the conformational change that exposes hydrophobic regions and leads to interaction with the respective targets. Sorcin forms homodimers through the association of the unpaired EF5 hand. Among the PEF proteins, sorcin is unique in that it contains potential phosphorylation sites by cAMP-dependent protein kinase (PKA), and it can form a tetramer at slightly acid pH values although remaining a stable dimer at neutral pH. Grancalcin (GCA) is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It can strongly interact with sorcin to form a heterodimer and further modulate the function of sorcin. GCA exists as homodimers in solution. It contains five EF-hand motifs attached to an N-terminal region of an approximately 50 residue-long segment rich in glycines and prolines. In contrast with sorcin, GCA binds two Ca2+ ions through its EF1 and EF3 hands.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 226533801  45 KKVFHILDKDRSGFIEEEELKFVLKGFtpdGRDLSDKETKALLAAGDKdgDGKIGADEF 103
Cdd:cd16181   73 KTTFMQYDRDRSGTVEPQELQQAIRSF---GYNLSPQALNVIVKRYSK--NGRITFDDF 126

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 226533801  46 KVFHILDKDRSGFIEEEELKFVLKGFTPDGRDLSDKE-------TKALLAAGDKDGDGKIGADEFA 104
Cdd:cd16179   99 KVWREYDKDNSGYIEADELKNFLKHLLKEAKRDNDVSedklieyTDTILQLFDRNKDGKLQLSEMA 164

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 226533801   43 DVKKVFHILDKDRSGFIEEEELKFVLK 69
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLK 27