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 1002239009 191 LVDSFVFLDKNKDGYVSKNEMIQAINETigGERSSGRIGMKRFEEMDWDKNGTVTFKEFLFAFT 254
Cdd:cd00051     2 LREAFRLFDKDGDGTISADELKAALKSL--GEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1002239009 188 FETLVDSFVFLDKNKDGYVSKNEMIQAINETIGGERSSGRIGMKRFEEMDWDKNGTVTFKEFLFAFT 254
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

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 1002239009 191 LVDSFVFLDKNKDGYVSKNEMIQAINETigGERSSGRIGMKRFEEMDWDKNGTVTFKEFLFAFT 254
Cdd:cd00051     2 LREAFRLFDKDGDGTISADELKAALKSL--GEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

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 1002239009 102 RIIFQQFDEDSNGEIDQQELKHCFQKLDISFTDEEIKDLFQACDIYENMGMKFNEFIVFL 161
Cdd:cd15898     3 RRQWIKADKDGDGKLSLKEIKKLLKRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELY 62

calmodulin; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002239009  95 DESLRNCRIIFQQFDEDSNGEIDQQELKHCFQKLDISFTDEEIKDLFQACDIYENMGMKFNEFIVFLclvyllndplvse 174
Cdd:PTZ00184    7 EEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLM------------- 73

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1002239009 175 ARKrMGLGSLEptfETLVDSFVFLDKNKDGYVSKNEMIQAIneTIGGERSSGRIGMKRFEEMDWDKNGTVTFKEF 249
Cdd:PTZ00184   74 ARK-MKDTDSE---EEIKEAFKVFDRDGNGFISAAELRHVM--TNLGEKLTDEEVDEMIREADVDGDGQINYEEF 142

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 1002239009 105 FQQFDEDSNGEIDQQELKHCFQKLDISFTDEEIKDLFQACDIYENMGMKFNEFIVF 160
Cdd:cd16202     6 FRKADKNGDGKLSFKECKKLLKKLNVKVDKDYAKKLFQEADTSGEDVLDEEEFVQF 61

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 1002239009  91 FPKIDESLRNCRIIFQQFDEDSNGEIDQQELKHCFQKLDISFTDEEIKDLFQACDIYENMGMKFNEFIvfLCLVYLLndp 170
Cdd:cd16180    59 FVGLWKYIQDWRRLFRRFDRDRSGSIDFNELQNALSSFGYRLSPQFVQLLVRKFDRRRRGSISFDDFV--EACVTLK--- 133

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1002239009 171 lvsearkrmglgsleptfeTLVDSFVFLDKNKDGYV 206
Cdd:cd16180   134 -------------------RLTDAFRKYDTNRTGYA 150

EF-hand, calcium binding motif, found in CREC-EF hand family; The CREC (Cab45/reticulocalbin/ERC45/calumenin)-EF hand family contains a group of six EF-hand, low-affinity Ca2+-binding proteins, including reticulocalbin (RCN-1), ER Ca2+-binding protein of 55 kDa (ERC-55, also known as TCBP-49 or E6BP), reticulocalbin-3 (RCN-3), Ca2+-binding protein of 45 kDa (Cab45 and its splice variant Cab45b), and calumenin ( also known as crocalbin or CBP-50). The proteins are not only localized in various parts of the secretory pathway, but also found in the cytosolic compartment and at the cell surface. They interact with different ligands or proteins and have been implicated in the secretory process, chaperone activity, signal transduction as well as in a large variety of disease processes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002239009  96 ESLRNCRIIFQQFDEDSNGEIDQQELKHCFQKLDISFTDEEIKDLFQACDIYENMGMKFNEFIV-FLCLVYLLNDPLVSE 174
Cdd:cd15899    32 ESKRRLGVIVSKMDVDKDGFISAKELHSWILESFKRHAMEESKEQFRAVDPDEDGHVSWDEYKNdTYGSVGDDEENVADN 111

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1002239009 175 ARKRmglgslEPTFETLVDS---FVFLDKNKDGYVSKNEMIQAINEtiggERSSgriGMKRF------EEMDWDKNGTVT 245
Cdd:cd15899   112 IKED------EEYKKLLLKDkkrFEAADQDGDLILTLEEFLAFLHP----EESP---YMLDFviketlEDLDKNGDGFIS 178

                  ....*
gi 1002239009 246 FKEFL 250
Cdd:cd15899   179 LEEFI 183

EF-hand domain;

                          10        20
                  ....*....|....*....|....*...
gi 1002239009 102 RIIFQQFDEDSNGEIDQQELKHCFQKLD 129
Cdd:pfam13405   3 REAFKLFDKDGDGKISLEELRKALRSLG 30

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1002239009  82 KSFNSVIMKFPKIDESLRNcriIFQQFDEDSNGEIDQQELKHCFQKLDIS---FTDEEIKDLFQACD 145
Cdd:cd16251    20 KKFFEHVGLKQKSEDQIKK---VFQILDKDKSGFIEEEELKYILKGFSIAgrdLTDEETKALLAAGD 83