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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1050115335   7 EEQIAEFKEAFSLFDKDGDGTITTKELGTVMRslgqnpteAELQDMINEVDADGNGTIDFPEFLTMMARKMKDTDsEEEI 86
Cdd:COG5126     1 DLQRRKLDRRFDLLDADGDGVLERDDFEALFR--------RLWATLFSEADTDGDGRISREEFVAGMESLFEATV-EPFA 71

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1050115335  87 REAFRVFDKDGNGYISAAELRHVMTNLGekLTDEEVDEMIREADIDGDGQVNYEEFVQMMT 147
Cdd:COG5126    72 RAAFDLLDTDGDGKISADEFRRLLTALG--VSEEEADELFARLDTDGDGKISFEEFVAAVR 130

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1050115335  83 EEEIREAFRVFDKDGNGYISAAELRHVMTNL--GEKLTDEEVDEMIREADIDGDGQVNYEEFVQMMT 147
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLeeGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

XopAW family type III secretion system calcium-binding effector;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1050115335  39 SLGQNPTEAELQ-DMINEVDADGNGTIDFPEFLTMMARKmKDTDSEEEIREAFRVFDKDGNGYISAAELRHVMTN----L 113
Cdd:NF041410   18 SSTSSARSQQFQkQLFAKLDSDGDGSVSQDELSSALSSK-SDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAPPppppP 96

                          90       100
                  ....*....|....*....|....*....
gi 1050115335 114 GEKLTDEEVDEMIREADIDGDGQVNYEEF 142
Cdd:NF041410   97 DQAPSTELADDLLSALDTDGDGSISSDEL 125

XopAW family type III secretion system calcium-binding effector;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1050115335  90 FRVFDKDGNGYISAAELRHVMTNLGEKLTDEEVDEMIREADIDGDGQVNYEEFVQMMT 147
Cdd:NF041410   33 FAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAP 90

centrin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1050115335   4 QLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTMMARKMKDTDSE 83
Cdd:PTZ00183   10 GLTEDQKKEIREAFDLFDTDGSGTIDPKELKVAMRSLGFEPKKEEIKQMIADVDKDGSGKIDFEEFLDIMTKKLGERDPR 89

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1050115335  84 EEIREAFRVFDKDGNGYISAAELRHVMTNLGEKLTDEEVDEMIREADIDGDGQVNYEEFVQMMTAK 149
Cdd:PTZ00183   90 EEILKAFRLFDDDKTGKISLKNLKRVAKELGETITDEELQEMIDEADRNGDGEISEEEFYRIMKKT 155

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 1050115335  85 EIREAFRVFDKDGNGYISAAELRHVMTNLGEKLTDEEVDEMIREADIDGDGQVNYEEFVQMMT 147
Cdd:cd00051     1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

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 1050115335  12 EFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAE-LQDMINEVDADGNGTIDFPEFltmmarkmKDTDSE-EEIREA 89
Cdd:cd16180     1 ELRRIFQAVDRDRSGRISAKELQRALSNGDWTPFSIEtVRLMINMFDRDRSGTINFDEF--------VGLWKYiQDWRRL 72

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1050115335  90 FRVFDKDGNGYISAAELRHVMTNLGEKLTDEEVDEMIREADIDGDGQVNYEEFVQMMT 147
Cdd:cd16180    73 FRRFDRDRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDFVEACV 130

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 1050115335  62 GTIDFPEFLTMMARKMKDTDSEEEIREAFRVFDKDGNGYISAAELRHVMTNLGEK-----LTDEEVDEMIREADIDGDGQ 136
Cdd:cd16252    15 GSFNYSKFFEYMQKFQTSEQQEEAIRKAFQMLDKDKSGFIEWNEIKYILSTVPSSmpvapLSDEEAEAMIQAADTDGDGR 94

                          90
                  ....*....|.
gi 1050115335 137 VNYEEFVQMMT 147
Cdd:cd16252    95 IDFQEFSDMVK 105

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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1050115335  13 FKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTMMARKMkdtdSEEEIREAFRV 92
Cdd:cd15898     2 LRRQWIKADKDGDGKLSLKEIKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELYKSLT----ERPELEPIFKK 77

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1050115335  93 FDKDGNGYISAAELRHVMTN-LGEKLTDEEVDEMIREADIDG-DGQVNYEEFVQMM 146
Cdd:cd15898    78 YAGTNRDYMTLEEFIRFLREeQGENVSEEECEELIEKYEPEReNRQLSFEGFTNFL 133

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 1050115335  13 FKEAFSLFDKDGDGTITTKELGTVMRSL-----GQNPTEAELQDMINEV----DADGNGTIDFPEFLTMMA--------- 74
Cdd:cd15902     1 FMEVWMHFDADGNGYIEGKELDSFLRELlkalnGKDKTDDEVAEKKKEFmekyDENEDGKIEIRELANILPteenflllf 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1050115335  75 RKMKDTDSEEEIREAFRVFDKDGNGYISAAELRHVMTNLGEKL--------TDEEVDEMIREADIDGDGQVNYEEFVQMM 146
Cdd:cd15902    81 RREQPLISSVEFMKIWRKYDTDGSGFIEAKELKGFLKDLLLKNkkhvsppkLDEYTKLILKEFDANKDGKLELDEMAKLL 160

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1050115335  62 GTIDFPEFLTMMARKMKdtdSEEEIREAFRVFDKDGNGYISAAELRHVMTNL---GEKLTDEEVDEMIREADIDGDGQVN 138
Cdd:cd16251    15 GSFNYKKFFEHVGLKQK---SEDQIKKVFQILDKDKSGFIEEEELKYILKGFsiaGRDLTDEETKALLAAGDTDGDGKIG 91

                          90
                  ....*....|
gi 1050115335 139 YEEFVQMMTA 148
Cdd:cd16251    92 VEEFATLVAG 101

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1050115335  49 LQDMINEVDADGNGTIDFPEFLTMMARkmkdtdseeEIREAFRVFDKDGNGYISAAELRHVMTNLGEKLTDEEVDEMIRE 128
Cdd:COG5126     7 LDRRFDLLDADGDGVLERDDFEALFRR---------LWATLFSEADTDGDGRISREEFVAGMESLFEATVEPFARAAFDL 77

                          90       100
                  ....*....|....*....|
gi 1050115335 129 ADIDGDGQVNYEEFVQMMTA 148
Cdd:COG5126    78 LDTDGDGKISADEFRRLLTA 97

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1050115335   1 MADQLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGqnPTEAELQDMINEVDADGNGTIDFPEFLTMMA 74
Cdd:COG5126    59 MESLFEATVEPFARAAFDLLDTDGDGKISADEFRRLLTALG--VSEEEADELFARLDTDGDGKISFEEFVAAVR 130

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 1050115335  10 IAEFKEAFSLFDKDGDGTITTKELgtvmrSLGQNPTE------AELQDMINEVDADGNGTIDFPEFLTMMArkmKDTDSE 83
Cdd:cd16227   121 LEDDKEMFEAADLNKDGKLDKTEF-----SAFQHPEEyphmhpVLIEQTLRDKDKDNDGFISFQEFLGDRA---GHEDKE 192

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1050115335  84 EEIREAFRV---FDKDGNGYISAAELRHVMTNLGEKLTDEEVDEMIREADIDGDGQVNYEEFV 143
Cdd:cd16227   193 WLLVEKDRFdedYDKDGDGKLDGEEILSWLVPDNEEIAEEEVDHLFASADDDHDDRLSFDEIL 255

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        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1050115335  82 SEEEIREAFRVFDKDGNGYISAAELRHVMTNL---GEKLTDEEVDEMIREADIDGDGQVNYEEFVQMMTA 148
Cdd:cd16255    32 SADDVKKVFEIIDQDKSGFIEEEELKLFLQNFssgARELTDAETKAFLKAGDSDGDGKIGVEEFQALVKA 101

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 1050115335  11 AEFKEAFSLFDKDGDGTITTKELGTVMRSL--------GQNPTEAELQDMINEVDADGNGTIDFPE----------FLTM 72
Cdd:cd15902    90 VEFMKIWRKYDTDGSGFIEAKELKGFLKDLllknkkhvSPPKLDEYTKLILKEFDANKDGKLELDEmakllpvqenFLLK 169

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1050115335  73 MARKMKDTDSEEEIREAFRVFDKDGNGYISAAELRHVMTNLGEKLTDEE--------VDEMIREADIDGDGQVNYEEFVQ 144
Cdd:cd15902   170 FQILGAMDLTKEDFEKVFEHYDKDNNGVIEGNELDALLKDLLEKNKADIdkpdlenfRDAILRACDKNKDGKIQKTELAL 249

                  ....*
gi 1050115335 145 MMTAK 149
Cdd:cd15902   250 FLSAK 254

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1050115335  13 FKEAFSLFDKDGDGTITTKELGTVMR------SLGQNPTEAELQDMINEVD----------ADGNGTIDFPEFLTMMARK 76
Cdd:cd15900     2 FEIAFKMFDLDGDGELDKEEFNKVQSiirsqtSVGQRHRDHTNGESTKLGMnstlaryffgKDGKQKLSIEKFLEFQENL 81

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1050115335  77 MKDTDseeEIREAFRvFDKDGNGYISAAELRHVM-TNLGEKLTDEEVDEMIREADIDGDGQVNYEEFVQMM 146
Cdd:cd15900    82 QEEID---DVDTALT-FYHLAGASIDRKTFKRAAkVVAGVELSDHVVDVVFTIFDEDGDGILSHKEFISVM 148

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 1050115335  10 IAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTMMARKMKDTDseeeireA 89
Cdd:cd16180    66 IQDWRRLFRRFDRDRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDFVEACVTLKRLTD-------A 138

                          90
                  ....*....|..
gi 1050115335  90 FRVFDKDGNGYI 101
Cdd:cd16180   139 FRKYDTNRTGYA 150

EF-hand, calcium binding motif, found in peflin and similar proteins; Peflin, also termed penta-EF hand (PEF) protein with a long N-terminal hydrophobic domain, or penta-EF hand domain-containing protein 1, is a ubiquitously expressed 30-kD PEF protein containing five EF-hand motifs in its C-terminal domain and a longer N-terminal hydrophobic domain (NHB domain) than any other member of the PEF family. The NHB domain harbors nine repeats of a nonapeptide (A/PPGGPYGGP). Peflin may modulate the function of ALG-2 in Ca2+ signaling. It exists only as a heterodimer with ALG-2, and binds two Ca2+ ions through its EF1 and EF3 hands. Its additional EF5 hand is unpaired and does not bind Ca2+ ion but mediates the heterodimerization with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. In lower vertebrates, peflin may interact with transient receptor potential N (TRPN1), suggesting a potential role of peflin in fast transducer channel adaptation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1050115335  17 FSLFDKDGDGTITTKEL-GTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFltmmarkmkdtdSE-----EEIREAF 90
Cdd:cd16184     6 FQAVDRDRSGKISAKELqQALVNGNWSHFNDETCRLMIGMFDKDKSGTIDIYEF------------QAlwnyiQQWKQVF 73

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1050115335  91 RVFDKDGNGYISAAELRHVMTNLGEKLTDEEVDEMIREADIDGDGQVNYEEFVQ 144
Cdd:cd16184    74 QQFDRDRSGSIDENELHQALSQMGYRLSPQFVQFLVSKYDPRARRSLTLDQFIQ 127

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 1050115335  62 GTIDFPEFLTMMARKMKdtdSEEEIREAFRVFDKDGNGYISAAELRHVMTNL---GEKLTDEEVDEMIREADIDGDGQVN 138
Cdd:cd16254    15 DSFDYKKFFEMVGLKKK---SADDVKKVFHILDKDKSGFIEEDELKFVLKGFspdGRDLSDKETKALLAAGDKDGDGKIG 91

                  ....*...
gi 1050115335 139 YEEFVQMM 146
Cdd:cd16254    92 IDEFATLV 99

EF-hand, calcium binding motif, found in calumenin, reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins; The family corresponds to a group of six EF-hand Ca2+-binding proteins, including calumenin (also known as crocalbin or CBP-50), reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins. Calumenin is an endo/sarcoplasmic reticulum (ER/SR) resident low-affinity Ca2+-binding protein that contains six EF-hand domains and a C-terminal SR retention signal His-Asp-Glu-Phe (HDEF) tetrapeptide. It functions as a novel regulator of SERCA2, and its expressional changes are tightly coupled with Ca2+-cycling of cardiomyocytes. It is also broadly involved in haemostasis and in the pathophysiology of thrombosis. Moreover, the extracellular calumenin acts as a suppressor of cell migration and tumor metastasis. RCN-1 is an endoplasmic reticulum resident Ca2+-binding protein with a carboxyl-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide signal. It acts as a potential negative regulator of B-RAF activation and can negatively modulate cardiomyocyte hypertrophy by inhibition of the mitogen-activated protein kinase signalling cascade. It also plays a key role in the development of doxorubicin-associated resistance. RCN-3 is a putative six EF-hand Ca2+-binding protein that contains five RXXR (X is any amino acid) motifs and a C-terminal ER retrieval signal HDEL tetrapeptide. The RXXR motif represents the target sequence of subtilisin-like proprotein convertases (SPCs). RCN-3 is specifically bound to the paired basic amino-acid-cleaving enzyme-4 (PACE4) precursor protein and plays an important role in the biosynthesis of PACE4.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1050115335  14 KEAFSLFDKDGDGTITTKELGTVMrslgqNPTEAE------LQDMINEVDADGNGTIDFPEFLTMMARK---MKDTDSEE 84
Cdd:cd16226   122 ERRWKAADQDGDGKLTKEEFTAFL-----HPEEFPhmrdivVQETLEDIDKNKDGFISLEEYIGDMYRDddeEEDPDWVK 196

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1050115335  85 EIREAFRVF-DKDGNGYISAAELRHVMTNLGEKLTDEEVDEMIREADIDGDGQVNYEE 141
Cdd:cd16226   197 SEREQFKEFrDKNKDGKMDREEVKDWILPEDYDHAEAEAKHLIYEADDDKDGKLTKEE 254

Eps15 homology domain; found in proteins implicated in endocytosis, vesicle transport, and signal transduction. The alignment contains a pair of EF-hand motifs, typically one of them is canonical and binds to Ca2+, while the other may not bind to Ca2+. A hydrophobic binding pocket is formed by residues from both EF-hand motifs. The EH domain binds to proteins containing NPF (class I), [WF]W or SWG (class II), or H[TS]F (class III) sequence motifs.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1050115335  88 EAFRVFDKDGNGYISAAELRHVMTNLGekLTDEEVDEMIREADIDGDGQVNYEEFV 143
Cdd:cd00052     3 QIFRSLDPDGDGLISGDEARPFLGKSG--LPRSVLAQIWDLADTDKDGKLDKEEFA 56

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
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1050115335  86 IREAFRVFDKDGNGYISAAELRHVMTNLGEKLTDEEVDEMIREADIDGDGQVNYEEFVQ 144
Cdd:cd16202     2 LKDQFRKADKNGDGKLSFKECKKLLKKLNVKVDKDYAKKLFQEADTSGEDVLDEEEFVQ 60

The penta-EF hand (PEF) family; The penta-EF hand (PEF) family contains a group of five EF-hand calcium-binding proteins, including several classical calpain large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14), two calpain small subunits (CAPNS1 and CAPNS2), as well as non-calpain PEF proteins, ALG-2 (apoptosis-linked gene 2, also termed programmed cell death protein 6, PDCD6), peflin, sorcin, and grancalcin. Based on the sequence similarity of EF1 hand, ALG-2 and peflin have been classified into group I PEF proteins. Calcium-dependent protease calpain subfamily members, sorcin and grancalcin, are group II PEF proteins. Calpains (EC 3.4.22.17) are calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates. They have been implicated in a number of physiological processes such as cell cycle progression, remodeling of cytoskeletal-cell membrane attachments, signal transduction, gene expression and apoptosis. ALG-2 is a pro-apoptotic factor that forms a homodimer in the cell or a heterodimer with its closest paralog peflin through their EF5s. Peflin is a 30-kD PEF protein with a longer N-terminal hydrophobic domain than any other member of the PEF family, and it contains nine nonapeptide (A/PPGGPYGGP) repeats. It exists only as a heterodimer with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. ALG-2 interacts with various proteins in a Ca2+-dependent manner. Sorcin (for soluble resistance-related calcium binding protein) is a soluble resistance-related calcium-binding protein that participates in the regulation of calcium homeostasis in cells. Grancalcin is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It plays a key role in leukocyte-specific functions that are responsible for host defense. Grancalcin can form a heterodimer together with sorcin. Members in this family contain five EF-hand motifs attached to an N-terminal region of variable length containing one or more short Gly/Pro-rich sequences. These proteins form homodimers or heterodimers through pairing between the 5th EF-hands from the two molecules. Unlike calmodulin, the PEF domains do not undergo major conformational changes upon binding Ca2+.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1050115335  10 IAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEaELQDMINEVDADGNGTIDFPEFLTMMARKmkdtdseEEIREA 89
Cdd:cd15897    69 IKAWQEIFRTYDTDGSGTIDSNELRQALSGAGYRLSE-QTYDIIIRRYDRGRGNIDFDDFIQCCVRL-------QRLTDA 140

                          90
                  ....*....|..
gi 1050115335  90 FRVFDKDGNGYI 101
Cdd:cd15897   141 FRRYDKDQDGQI 152

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 1050115335  62 GTIDFPEFLTMMARKMKdtdSEEEIREAFRVFDKDGNGYISAAELRHVMTNLGEK---LTDEEVDEMIREADIDGDGQVN 138
Cdd:cd16253    15 DSFDHKAFFKAVGLSKK---SPADIKKVFNILDQDKSGFIEEEELKLFLKNFSDGarvLSDKETKNFLAAGDSDGDGKIG 91

                          90
                  ....*....|
gi 1050115335 139 YEEFVQMMTA 148
Cdd:cd16253    92 VDEFKSMVKA 101

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

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1050115335    5 LTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTeaELQDMINEVDADGNGTIDFPEF-LTM 72
Cdd:smart00027   4 ISPEDKAKYEQIFRSLDKNQDGTVTGAQAKPILLKSGLPQT--LLAKIWNLADIDNDGELDKDEFaLAM 70

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1050115335  11 AEFKEAFSLFDKDGDGTITTKELGTVMRSLGQ--------NPTEAELQDMINEVDADGNGTIDfpefLTMMARKMKDTD- 81
Cdd:cd16176    85 EEFMQTWRKYDADHSGFIEADELKSFLKDLLKkankpfdeSKLEEYTHTMLKMFDSNNDGKLG----LTEMARLLPVQEn 160

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1050115335  82 ----------SEEEIREAFRVFDKDGNGYISAAELRHVMTNLGEK 116
Cdd:cd16176   161 fllkfqgvkmCGKEFNKIFELYDQDGNGYIDENELDALLKDLCEK 205

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 1050115335   12 EFKEAFSLFDKDGDGTITTKELGTVMRSL 40
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

EF-hand, calcium binding motif, found in uncharacterized calglandulin-like proteins; The family corresponds to a group of uncharacterized calglandulin-like proteins. Although their biological function remain unclear, they show high sequence similarity with human calglandulin-like protein GAGLP, which is an ortholog of calglandulin from the venom glands of Bothrops insularis snake. Both GAGLP and calglandulin are putative Ca2+-binding proteins with four EF-hand motifs. However, members in this family contain only three EF-hand motifs. In this point, they may belong to the parvalbumin-like EF-hand family, which is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix).

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1050115335   4 QLTEEQIAEFKEAFSLFDKDGDGTITTKE----LGTVMRSLGQNP-TEAELQDMINEVDADGNGTIDFPEFLTM 72
Cdd:cd16252    30 QTSEQQEEAIRKAFQMLDKDKSGFIEWNEikyiLSTVPSSMPVAPlSDEEAEAMIQAADTDGDGRIDFQEFSDM 103

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 1050115335  14 KEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTMMARKMKdtdsEEEIREAFRVF 93
Cdd:cd16202     3 KDQFRKADKNGDGKLSFKECKKLLKKLNVKVDKDYAKKLFQEADTSGEDVLDEEEFVQFYNRLTK----RPEIEELFKKY 78

                          90
                  ....*....|....*...
gi 1050115335  94 DKDGnGYISAAELRHVMT 111
Cdd:cd16202    79 SGDD-EALTVEELRRFLQ 95

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 1050115335   85 EIREAFRVFDKDGNGYISAAELRHVMTNL 113
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29