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 11545811 115 KLHYAFQLYDLDRDGKISRHEMLQVLRLMvGVQVTEEQLENIadrtVQEADEDGDGAVSFVEFTK 179
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSL-GEGLSEEEIDEM----IREVDKDGDGKIDFEEFLE 60

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11545811   35 FRALDRNKKGYLSRMDLQQI-GALAVNP----LGDRIIESFFpDGSQRVDFPGFVRVLAhfRPVEDEDTETQdpkkpepl 109
Cdd:PTZ00184  17 FSLFDKDGDGTITTKELGTVmRSLGQNPteaeLQDMINEVDA-DGNGTIDFPEFLTLMA--RKMKDTDSEEE-------- 85

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 11545811  110 nsrrnkLHYAFQLYDLDRDGKISRHEMLQVLRLMvGVQVTEEQleniADRTVQEADEDGDGAVSFVEFTKSL 181
Cdd:PTZ00184  86 ------IKEAFKVFDRDGNGFISAAELRHVMTNL-GEKLTDEE----VDEMIREADVDGDGQINYEEFVKMM 146

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 11545811 115 KLHYAFQLYDLDRDGKISRHEMLQVLRLMvGVQVTEEQLENIadrtVQEADEDGDGAVSFVEFTK 179
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSL-GEGLSEEEIDEM----IREVDKDGDGKIDFEEFLE 60

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11545811   35 FRALDRNKKGYLSRMDLQQI-GALAVNP----LGDRIIESFFpDGSQRVDFPGFVRVLAhfRPVEDEDTETQdpkkpepl 109
Cdd:PTZ00184  17 FSLFDKDGDGTITTKELGTVmRSLGQNPteaeLQDMINEVDA-DGNGTIDFPEFLTLMA--RKMKDTDSEEE-------- 85

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 11545811  110 nsrrnkLHYAFQLYDLDRDGKISRHEMLQVLRLMvGVQVTEEQleniADRTVQEADEDGDGAVSFVEFTKSL 181
Cdd:PTZ00184  86 ------IKEAFKVFDRDGNGFISAAELRHVMTNL-GEKLTDEE----VDEMIREADVDGDGQINYEEFVKMM 146

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 11545811 115 KLHYAFQLYDLDRDGKISRHEMLQVLRLMvGVQVTEEQLENIadrtVQEADEDGDGAVSFVEFTK 179
Cdd:cd15898   1 WLRRQWIKADKDGDGKLSLKEIKKLLKRL-NIRVSEKELKKL----FKEVDTNGDGTLTFDEFEE 60

EF-hand domain pair;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 11545811   128 DGKISRHEMLQVLRLMVGVQVTEEQLENIadrtVQEADEDGDGAVSFVEFTKSLEK 183
Cdd:pfam13833   2 KGVITREELKRALALLGLKDLSEDEVDIL----FREFDTDGDGYISFDEFCVLLER 53

EF-hand, calcium binding motif, found in homologs of mammalian apoptosis-linked gene 2 protein (ALG-2); The family includes some homologs of mammalian apoptosis-linked gene 2 protein (ALG-2) mainly found in lower eukaryotes, such as a parasitic protist Leishmarua major and a cellular slime mold Dictyostelium discoideum. These homologs contains five EF-hand motifs. Due to the presence of unfavorable residues at the Ca2+-coordinating positions, their non-canonical EF4 and EF5 hands may not bind Ca2+. Two Dictyostelium PEF proteins are the prototypes of this family. They may bind to cytoskeletal proteins and/or signal-transducing proteins localized to detergent-resistant membranes named lipid rafts, and occur as monomers or weak homo- or heterodimers like ALG-2. They can serve as a mediator for Ca2+ signaling-related Dictyostehum programmed cell death (PCD).

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 11545811  35 FRALDRNKKGYLSRMDLQQIGALAVNPLG----DRIIESFFPDGSQRVDFPGFVRvLAHFrpvededtetqdpkkpepLN 110
Cdd:cd16185   6 FRAVDRDRSGSIDVNELQKALAGGGLLFSlataEKLIRMFDRDGNGTIDFEEFAA-LHQF------------------LS 66

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 11545811 111 SRRNklhyAFQLYDLDRDGKISRHEMLQVLRlMVGVQVTeeqlENIADRTVQEADEDGDGAVSFVEF 177
Cdd:cd16185  67 NMQN----GFEQRDTSRSGRLDANEVHEALA-ASGFQLD----PPAFQALFRKFDPDRGGSLGFDDY 124

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 11545811  28 LLRLHHRFRALDRNKKGYLSRMDLQQIGALAVNPLGDRII-----ESFFPDGSQRVDFPGFVRVLAHFRPVEDEdtetqd 102
Cdd:cd15899 122 LLKDKKRFEAADQDGDLILTLEEFLAFLHPEESPYMLDFViketlEDLDKNGDGFISLEEFISDPYSADENEEE------ 195

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 11545811 103 pkkPEPLNSRRNKLHyafQLYDLDRDGKISRHEMLQVLrlmvgVQVTEEQLENIADRTVQEADEDGDGAVSFVE 176
Cdd:cd15899 196 ---PEWVKVEKERFV---ELRDKDKDGKLDGEELLSWV-----DPSNQEIALEEAKHLIAESDENKDGKLSPEE 258

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 11545811 116 LHYAFQLYDLDRDGKISRHEMLQVLRLMvGVQVTEEQleniADRTVQEADEDGDGAVSFVEFTKSLEKM 184
Cdd:cd16202   2 LKDQFRKADKNGDGKLSFKECKKLLKKL-NVKVDKDY----AKKLFQEADTSGEDVLDEEEFVQFYNRL 65

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 11545811  35 FRALDRNKKGYLSRMDLQQI--GALAVNPLG----------DRIIESFFPDGSQRVDFPGFVRVLahfrPVEDEDTETQD 102
Cdd:cd15902  96 WRKYDTDGSGFIEAKELKGFlkDLLLKNKKHvsppkldeytKLILKEFDANKDGKLELDEMAKLL----PVQENFLLKFQ 171

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 11545811 103 PKKPEPLnsRRNKLHYAFQLYDLDRDGKISRHEMLQVLR-LMVGVQ--VTEEQLENIADRTVQEADEDGDGAVSFVE 176
Cdd:cd15902 172 ILGAMDL--TKEDFEKVFEHYDKDNNGVIEGNELDALLKdLLEKNKadIDKPDLENFRDAILRACDKNKDGKIQKTE 246