calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15233402   34 FDLFDKNGDGFITVEELSQALTRLGLNADLSDLKSTVESYIQPGNTGLNFDDFSSL-HKTLDDSffggacgggeneddps 112
Cdd:PTZ00184  17 FSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLmARKMKDT---------------- 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 15233402  113 saaENESDLAEAFKVFDENGDGFISARELQTVLKKLGlpEGGEMERVEKMIVSVDRNQDGRVDFFEFKNMM 183
Cdd:PTZ00184  81 ---DSEEEIKEAFKVFDRDGNGFISAAELRHVMTNLG--EKLTDEEVDEMIREADVDGDGQINYEEFVKMM 146

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15233402   34 FDLFDKNGDGFITVEELSQALTRLGLNADLSDLKSTVESYIQPGNTGLNFDDFSSL-HKTLDDSffggacgggeneddps 112
Cdd:PTZ00184  17 FSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLmARKMKDT---------------- 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 15233402  113 saaENESDLAEAFKVFDENGDGFISARELQTVLKKLGlpEGGEMERVEKMIVSVDRNQDGRVDFFEFKNMM 183
Cdd:PTZ00184  81 ---DSEEEIKEAFKVFDRDGNGFISAAELRHVMTNLG--EKLTDEEVDEMIREADVDGDGQINYEEFVKMM 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 15233402 120 DLAEAFKVFDENGDGFISARELQTVLKKLGLPEGgeMERVEKMIVSVDRNQDGRVDFFEFKNMMR 184
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLS--EEEIDEMIREVDKDGDGKIDFEEFLELMA 63

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 15233402     30 LQRIFDLFDKNGDGFITVEELSQALTRL 57
Cdd:smart00054   2 LKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15233402   34 FDLFDKNGDGFITVEELSQALTRLGLNADLSDLKSTVESYIQPGNTGLNFDDFSSL-HKTLDDSffggacgggeneddps 112
Cdd:PTZ00184  17 FSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMINEVDADGNGTIDFPEFLTLmARKMKDT---------------- 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 15233402  113 saaENESDLAEAFKVFDENGDGFISARELQTVLKKLGlpEGGEMERVEKMIVSVDRNQDGRVDFFEFKNMM 183
Cdd:PTZ00184  81 ---DSEEEIKEAFKVFDRDGNGFISAAELRHVMTNLG--EKLTDEEVDEMIREADVDGDGQINYEEFVKMM 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 15233402 120 DLAEAFKVFDENGDGFISARELQTVLKKLGLPEGgeMERVEKMIVSVDRNQDGRVDFFEFKNMMR 184
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLS--EEEIDEMIREVDKDGDGKIDFEEFLELMA 63

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 15233402   118 ESDLAEAFKVFDENGDGFISARELQTVLKKLGLPEGGEMERVEKMIVSVDRNQDGRVDFFEFKNMMR 184
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

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 15233402  30 LQRIFDLFDKNGDGFITVEELSQALTRLGLNADLSDLKSTVESYIQPGNTGLNFDDFSSLHKTLddsffggacgggened 109
Cdd:cd16185   2 LRQWFRAVDRDRSGSIDVNELQKALAGGGLLFSLATAEKLIRMFDRDGNGTIDFEEFAALHQFL---------------- 65

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 15233402 110 dpssaaeneSDLAEAFKVFDENGDGFISARELQTVLKKLG--LPEggemERVEKMIVSVDRNQDGRVDFFEFKNM 182
Cdd:cd16185  66 ---------SNMQNGFEQRDTSRSGRLDANEVHEALAASGfqLDP----PAFQALFRKFDPDRGGSLGFDDYIEL 127

calmodulin; Provisional

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 15233402  116 ENESDLAEAFKVFDENGDGFISARELQTVLKKLGL-PEGGEMervEKMIVSVDRNQDGRVDFFEFKNMM 183
Cdd:PTZ00184   8 EQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQnPTEAEL---QDMINEVDADGNGTIDFPEFLTLM 73

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 15233402    29 RLQRIFDLFDKNGDGFITVEELSQALTRLGLNADLSD--LKSTVESYIQPGNTGLNFDDF 86
Cdd:pfam13499   3 KLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEPLSDeeVEELFKEFDLDKDGRISFEEF 62

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
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 15233402 120 DLAEAFKVFDENGDGFISARELQTVLKKLGLPEGGEMerVEKMIVSVDRNQDGRVDFFEFKNM 182
Cdd:cd16185   1 ELRQWFRAVDRDRSGSIDVNELQKALAGGGLLFSLAT--AEKLIRMFDRDGNGTIDFEEFAAL 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 15233402 120 DLAEAFKVFDENGDGFISARELQTVLkKLGLPEGGEMERVEKMIVSVDRNQDGRVDFFEFKNMMRTV 186
Cdd:cd16180   1 ELRRIFQAVDRDRSGRISAKELQRAL-SNGDWTPFSIETVRLMINMFDRDRSGTINFDEFVGLWKYI 66

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 15233402     30 LQRIFDLFDKNGDGFITVEELSQALTRL 57
Cdd:smart00054   2 LKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15233402   30 LQRIFDLFDKNGDGFITVEELSQALTRLGLNADLSDLKSTVESYIQPGNTGLNFDDFSSLHKTlddsffggacgggenED 109
Cdd:NF041410  29 QKQLFAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAPP---------------PP 93

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 15233402  110 DPSSAAENESDLAEAFKVFDENGDGFISARELQTvlkklGLPEGGEMERVEKMIVSVDRNQDGRVDFFEFK 180
Cdd:NF041410  94 PPPDQAPSTELADDLLSALDTDGDGSISSDELSA-----GLTSAGSSADSSQLFSALDSDGDGSVSSDELA 159

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 15233402   120 DLAEAFKVFDENGDGFISARELQTVLKKL 148
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKKL 29

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 15233402  29 RLQRIFDLFDKNGDGFITVEELSQALTRLGLNADLSDLKSTVESYIQPGNTGLNFDDFSslhktldDSFFGGACGGGENE 108
Cdd:cd15899  36 RLGVIVSKMDVDKDGFISAKELHSWILESFKRHAMEESKEQFRAVDPDEDGHVSWDEYK-------NDTYGSVGDDEENV 108

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 15233402 109 DDPSSAAENE----SDLAEAFKVFDENGDGFISARELQTVLKKlglPEGGEMER--VEKMIVSVDRNQDGRVDFFEF 179
Cdd:cd15899 109 ADNIKEDEEYkkllLKDKKRFEAADQDGDLILTLEEFLAFLHP---EESPYMLDfvIKETLEDLDKNGDGFISLEEF 182

EF-hand, calcium binding motif, found in apoptosis-linked gene 2 protein (ALG-2) and similar proteins; ALG-2, also termed programmed cell death protein 6 (PDCD6), or probable calcium-binding protein ALG-2, is one of the prototypic members of the penta EF-hand protein family. It is a widely expressed calcium-binding modulator protein associated with cell proliferation and death, as well as cell survival. ALG-2 acts as a pro-apoptotic factor participating in T cell receptor-, Fas-, and glucocorticoid-induced programmed cell death, and also serves as a useful molecular marker for the prognosis of cancers. Moreover, ALG-2 functions as a calcium ion sensor at endoplasmic reticulum (ER) exit sites, and modulates ER-stress-stimulated cell death and neuronal apoptosis during organ formation. Furthermore, ALG-2 can mediate the pro-apoptotic activity of cisplatin or tumor necrosis factor alpha (TNFalpha) through the down-regulation of nuclear factor-kappaB (NF-kappaB) expression. It also inhibits angiogenesis through PI3K/mTOR/p70S6K pathway by interacting of vascular endothelial growth factor receptor-2 (VEGFR-2). In addition, nuclear ALG-2 may participate in the post-transcriptional regulation of Inositol Trisphosphate Receptor Type 1 (IP3R1) pre-mRNA at least in part by interacting with CHERP (Ca2+ homeostasis endoplasmic reticulum protein) calcium-dependently. ALG-2 contains five serially repeated EF-hand motifs and interacts with various proteins, including ALG-2-interacting protein X (Alix), Fas, annexin XI, death-associated protein kinase 1 (DAPk1), Tumor susceptibility gene 101 (TSG101), Sec31A, phospholipid scramblase 3 (PLSCR3), the P-body component PATL1, and endosomal sorting complex required for transport (ESCRT)-III-related protein IST1, in a calcium-dependent manner. It forms a homodimer in the cell or a heterodimer with its closest paralog peflin. Among the PEF proteins, ALG-2 can bind three Ca2+ ions through its EF1, EF3, and EF5 hands, where it is unique in that its EF5 hand binds Ca2+ ion in a canonical coordination.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 15233402  31 QRIFDLFDKNGDGFITVEELSQALTRLG--LNADLSDLksTVESYIQPGNTGLNFDDF---SSLHKTLDDSF 97
Cdd:cd16183  70 QNCFRSFDRDNSGNIDKNELKQALTSFGyrLSDQFYDI--LVRKFDRQGRGTIAFDDFiqcCVVLQTLTDSF 139

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 15233402  89 LHKTLD-DSFFGGACGGgenEDDPSSAAENESDLAEAFKVFDENGDGFISARELQTVLKKlgLPEGGEMERVEKMIVSVD 167
Cdd:cd15899   7 LNSDYDhEAFLGKEEAE---EFDQLTPEESKRRLGVIVSKMDVDKDGFISAKELHSWILE--SFKRHAMEESKEQFRAVD 81

                        90       100
                ....*....|....*....|...
gi 15233402 168 RNQDGRVDFFEFKNMMRTVVIPS 190
Cdd:cd15899  82 PDEDGHVSWDEYKNDTYGSVGDD 104

EF hand;

                          10        20
                  ....*....|....*....|....*
gi 15233402   121 LAEAFKVFDENGDGFISARELQTVL 145
Cdd:pfam13202   1 LKDTFRQIDLNGDGKISKEELRRLL 25

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
                ....*....|....*....|....*....|....*....|....*....|....
gi 15233402 132 GDGFISARELQTVLKKLGLP---EGGEMERVEKMIVSVDRNQDGRVDFFEFKNM 182
Cdd:cd15897  12 DDGEISATELQQALSNVGWThfdLGFSLETCRSMIAMMDRDHSGKLNFSEFKGL 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 15233402 122 AEAFKVFDENGDGFISARELQTVLKKLGLPEGGEM-------ERVEKMIVSVDRNQDGRVDFFEFKNMMRT 185
Cdd:cd15902   2 MEVWMHFDADGNGYIEGKELDSFLRELLKALNGKDktddevaEKKKEFMEKYDENEDGKIEIRELANILPT 72

EF-hand motif found in phosphoinositide phospholipase C eta 1 (PI-PLC-eta1); PI-PLC-eta1, also termed 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-1, or phospholipase C-eta-1 (PLC-eta-1), or phospholipase C-like protein 3 (PLC-L3), is a neuron-specific PI-PLC that is most abundant in the brain, particularly in the hippocampus, habenula, olfactory bulb, cerebellum, and throughout the cerebral cortex. It is also expressed in the zona incerta and in the spinal cord. PI-PLC-eta1 may perform a fundamental role in the brain. It may also act in synergy with other PLC subtypes. For instance, it is activated via intracellular Ca2+ mobilization and then plays a role in the amplification of GPCR (G-protein-coupled receptor)-mediated PLC-beta signals. In addition, its activity can be stimulated by ionomycin. PI-PLC-eta1 contains an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core domain, a C2 domain, and a unique C-terminal tail that terminates with a PDZ-binding motif, a potential interaction site for other signaling proteins. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. The C-terminal tail harbors a number of proline-rich motifs which may interact with SH3 (Src homology 3) domain-containing proteins, as well as many serine/threonine residues, suggesting possible regulation of interactions by protein kinases/phosphatases.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 15233402  30 LQRIFDLFDKNGDGFITVEELSQALTRLGLNADLSDLKSTVESYIQPGNTG-LNFDDFSSLHKTL 93
Cdd:cd16220   2 VKQTFEEADKNGDGLLNIEEIYQLMHKLNVNLPRRKVRQMFQEADTDENQGtLTFEEFCVFYKMM 66

EF hand;

                          10        20
                  ....*....|....*....|...
gi 15233402    30 LQRIFDLFDKNGDGFITVEELSQ 52
Cdd:pfam13202   1 LKDTFRQIDLNGDGKISKEELRR 23

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 15233402  18 FRLRSPSLNALRLQRIFDLFDKNGDGFITVEELSQALTRLGLNADLSDLKSTVESYIqpgNTGLNFDDfSSLHKTLDDSF 97
Cdd:cd15902  80 FRREQPLISSVEFMKIWRKYDTDGSGFIEAKELKGFLKDLLLKNKKHVSPPKLDEYT---KLILKEFD-ANKDGKLELDE 155

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15233402  98 FGGACGGGENE----DDPSSAAENESDLAEAFKVFDENGDGFISARELQTVLKKLG-----LPEGGEMERVEKMIVSV-D 167
Cdd:cd15902 156 MAKLLPVQENFllkfQILGAMDLTKEDFEKVFEHYDKDNNGVIEGNELDALLKDLLeknkaDIDKPDLENFRDAILRAcD 235

                ....*..
gi 15233402 168 RNQDGRV 174
Cdd:cd15902 236 KNKDGKI 242

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 15233402  28 LRLQRIFDLFDKNGDGFITVEELSqALTRLGLNADLSD--LKSTVESYIQPGNTGLNFDDFSSLHKTLDdsffggacggg 105
Cdd:cd15899 123 LKDKKRFEAADQDGDLILTLEEFL-AFLHPEESPYMLDfvIKETLEDLDKNGDGFISLEEFISDPYSAD----------- 190

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 15233402 106 ENEDDPsSAAENESDLAEAFkvFDENGDGFISARELQTVLkklgLP--EGGEMERVEKMIVSVDRNQDGRVDFFE 178
Cdd:cd15899 191 ENEEEP-EWVKVEKERFVEL--RDKDKDGKLDGEELLSWV----DPsnQEIALEEAKHLIAESDENKDGKLSPEE 258

EF-hand, calcium binding motif, found in the hexa-EF hand proteins family; The hexa-EF hand proteins family, also named the calbindin sub-family, contains a group of six EF-hand Ca2+-binding proteins, including calretinin (CR, also termed 29 kDa calbindin), calbindin D28K (CB, also termed vitamin D-dependent calcium-binding protein, avian-type), and secretagogin (SCGN). CR is a cytosolic hexa-EF-hand calcium-binding protein predominantly expressed in a variety of normal and tumorigenic t-specific neurons of the central and peripheral nervous system. It is a multifunctional protein implicated in many biological processes, including cell proliferation, differentiation, and cell death. CB is highly expressed in brain tissue. It is a strong calcium-binding and buffering protein responsible for preventing a neuronal death as well as maintaining and controlling calcium homeostasis. SCGN is a six EF-hand calcium-binding protein expressed in neuroendocrine, pancreatic endocrine and retinal cells. It plays a crucial role in cell apoptosis, receptor signaling and differentiation. It is also involved in vesicle secretion through binding to various proteins, including interacts with SNAP25, SNAP23, DOC2alpha, ARFGAP2, rootletin, KIF5B, beta-tubulin, DDAH-2, ATP-synthase and myeloid leukemia factor 2. SCGN functions as a Ca2+ sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. Although the family members share a significant amount of secondary sequence homology, they display altered structural and biochemical characteristics, and operate in distinct fashions. CB contains six EF-hand motifs in a single globular domain, where EF-hands 1, 3, 4, 5 bind four calcium ions. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. They harbor two and four EF-hand motifs, respectively. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. Human SCGN simultaneously binds four calcium ions through its EF-hands 3, 4, 5 and 6 in one high affinity and three low affinity calcium-binding sites. In contrast, SCGNs in other lower eukaryotes, such as D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, are fully competent in terms of six calcium-binding.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15233402  32 RIFDLFDKNGDGFITVEELSQALTRLGLN--------ADLSDLKST-VESYIQPGNTGLNFDDFSSLHKTLDDSFFGGAC 102
Cdd:cd15902   3 EVWMHFDADGNGYIEGKELDSFLRELLKAlngkdktdDEVAEKKKEfMEKYDENEDGKIEIRELANILPTEENFLLLFRR 82

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 15233402 103 GGGEneddpssaaENESDLAEAFKVFDENGDGFISARELQTVLK------KLGLPEGGEMERVEKMIVSVDRNQDGRVDF 176
Cdd:cd15902  83 EQPL---------ISSVEFMKIWRKYDTDGSGFIEAKELKGFLKdlllknKKHVSPPKLDEYTKLILKEFDANKDGKLEL 153

                ...
gi 15233402 177 FEF 179
Cdd:cd15902 154 DEM 156

EF-hand motif found in phosphoinositide phospholipase C eta 2 (PI-PLC-eta2); PI-PLC-eta2, also termed 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase eta-2, or phosphoinositide phospholipase C-like 4, or phospholipase C-like protein 4 (PLC-L4), or phospholipase C-eta-2 (PLC-eta2), is a neuron-specific PI-PLC that is most abundant in the brain, particularly in the hippocampus, habenula, olfactory bulb, cerebellum, and throughout the cerebral cortex. It is also expressed in the pituitary gland, pineal gland, retina, and lung, as well as in neuroendocrine cells. PI-PLC-eta2 has been implicated in the regulation of neuronal differentiation/maturation. It is required for retinoic acid-stimulated neurite growth. It may also in part function downstream of G-protein-coupled receptors and play an important role in the formation and maintenance of the neuronal network in the postnatal brain. Moreover, PI-PLC-eta2 acts as a Ca2+ sensor that shows a canonical EF-loop directing Ca2+-sensitivity and thus can amplify transient Ca2+ signals. Its activation can be triggered either by intracellular calcium mobilization or by G beta-gamma signaling. PI-PLC-eta2 contains an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core domain, a C2 domain, and a unique C-terminal tail that terminates with a PDZ-binding motif, a potential interaction site for other signaling proteins. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. The C-terminal tail harbors a number of proline-rich motifs which may interact with SH3 (Src homology 3) domain-containing proteins, as well as many serine/threonine residues, suggesting possible regulation of interactions by protein kinases/phosphatases.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 15233402  30 LQRIFDLFDKNGDGFITVEELSQALTRLGLNADLSDLKSTVESYIQPGNTG-LNFDDFSSLHKTL 93
Cdd:cd16221   2 LKQTFDEADKNGDGSLSIGEVLQLLHKLNVNLPRQKVKQMFKEADTDDNQGtLGFEEFCAFYKMM 66