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 98985787  65 AEHVFRTFDANGDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDLDGNGYISKAEMLEIVQ 126
Cdd:cd00051   2 LREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

EF-hand domain pair;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 98985787    98 EQKLKWAFSMYDLDGNGYISKAEMLEIVQAIYkmvssvmkmpEDESTPEKRTEKIFRQMDTNRDGKLSLEEFIRGAK 174
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLE----------EGEPLSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

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 98985787    100 KLKWAFSMYDLDGNGYISKAEMLEIVQAI 128
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

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 98985787  65 AEHVFRTFDANGDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDLDGNGYISKAEMLEIVQ 126
Cdd:cd00051   2 LREAFRLFDKDGDGTISADELKAALKSLGEGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985787   73 DANGDGTIDFREFIIALSVTSR-GKLEQKLKWAFSMYDLDGNGYISKAEMLEIvqaiykMVSSVMKMPEDEstpekrTEK 151
Cdd:PTZ00184  57 DADGNGTIDFPEFLTLMARKMKdTDSEEEIKEAFKVFDRDGNGFISAAELRHV------MTNLGEKLTDEE------VDE 124

                         90       100
                 ....*....|....*....|
gi 98985787  152 IFRQMDTNRDGKLSLEEFIR 171
Cdd:PTZ00184 125 MIREADVDGDGQINYEEFVK 144

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985787   63 KFAEHVFRTFDANGDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDLDGNGYISKAEMleivqaiykmvSSVMKMP--- 139
Cdd:NF041410  27 QFQKQLFAKLDSDGDGSVSQDELSSALSSKSDDGSLIDLSELFSDLDSDGDGSLSSDEL-----------AAAAPPPppp 95

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 98985787  140 EDESTPEKRTEKIFRQMDTNRDGKLSLEEFIRGAKSDPS 178
Cdd:NF041410  96 PDQAPSTELADDLLSALDTDGDGSISSDELSAGLTSAGS 134

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 98985787  26 EIQEWYKGFLRDCpSGHLSMEEFKKI---YGNFFPYGDASKFaehvFRTFDANGDGTIDFREFiIALSvtsrgKLEQKLK 102
Cdd:cd16185   1 ELRQWFRAVDRDR-SGSIDVNELQKAlagGGLLFSLATAEKL----IRMFDRDGNGTIDFEEF-AALH-----QFLSNMQ 69

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985787 103 WAFSMYDLDGNGYISKAEMLEIVQAI-YKMVSSVMKmpedestpekrteKIFRQMDTNRDGKLSLEEFIR 171
Cdd:cd16185  70 NGFEQRDTSRSGRLDANEVHEALAASgFQLDPPAFQ-------------ALFRKFDPDRGGSLGFDDYIE 126

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 98985787    68 VFRTFDANGDGTIDFREFIIALSVTSRGK--LEQKLKWAFSMYDLDGNGYISKAEMLEIVQ 126
Cdd:pfam13499   7 AFKLLDSDGDGYLDVEELKKLLRKLEEGEplSDEEVEELFKEFDLDKDGRISFEEFLELYS 67

EF-hand, calcium binding motif, found in Drosophila melanogaster calbindin-32 (CBN) and similar proteins; CBN, the product of the cbn gene, is a Drosophila homolog to vertebrate neuronal six EF-hand calcium binding proteins. It is expressed through most of ontogenesis with a selective distribution in the nervous system and in a few small adult thoracic muscles. Its precise biological role remains unclear. CBN contains six EF-hand motifs, but some of them may not bind calcium ions due to the lack of key residues.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985787  64 FAEHVFRTFDANGDGTIDFREFIIALSVTSRGKLEQKLKWA-----------FSMYDLDGNGYISKAEM-------LEIV 125
Cdd:cd16179 142 YTDTILQLFDRNKDGKLQLSEMARLLPVKENFLCRPIFKGAgkltredidrvFALYDRDNNGTIENEELtgflkdlLELV 221

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 98985787 126 QAIYkmvssvmkmpeDESTPEKRTEKIFRQMDTNRDGKLSLEE 168
Cdd:cd16179 222 QEDY-----------DEQDLEEFKEIILRGWDFNNDGKISRKE 253

EF-hand-like motif found in the dystrophin/dystrobrevin/dystrotelin family; The dystrophin/dystrobrevin/dystrotelin family has been characterized by a compact cluster of domains comprising four EF-hand-like motifs and a ZZ-domain, followed by a looser region with two coiled-coils. Dystrophin is the founder member of this family. It is a sub-membrane cytoskeletal protein associated with the inner surface membrane. Dystrophin and its close paralog utrophin have a large N-terminal extension of actin-binding CH domains, up to 24 spectrin repeats, and a WW domain. Its further paralog, dystrophin-related protein 2 (DRP-2), retains only two of the spectrin repeats. Dystrophin, utrophin or DRP2 can form the core of a membrane-bound complex consisting of dystroglycan, sarcoglycans and syntrophins, known as the dystrophin-glycoprotein complex (DGC) that plays an important role in brain development and disease, as well as in the prevention of muscle damage. Dystrobrevins, including alpha- and beta-dystrobrevin, lack the large N-terminal extension found in dystrophin, but alpha-dystrobrevin has a characteristic C-terminal extension. Dystrobrevins are part of the DGC. They physically associate with members of the dystrophin family and with the syntrophins through their homologous C-terminal coiled coil motifs. In contrast, dystrotelins lack both the large N-terminal extension found in dystrophin and the obvious syntrophin-binding sites (SBSs). Dystrotelins are not critical for mammalian development. They may be involved in other forms of cytokinesis. Moreover, dystrotelin is unable to heterodimerize with members of the dystrophin or dystrobrevin families, or to homodimerize.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 98985787  71 TFDANGDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDlDGNGYISKAEMLEIVQAIYKMVS 133
Cdd:cd15901  62 LYDRNRTGCIRLLSVKIALITLCAASLLDKYRYLFGQLA-DSSGFISRERLTQFLQDLLQIPD 123

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 98985787  63 KFAEHVFRTFDANGDGTIDFREFIIALSV------TSRGKLEQKLKW-----AFSMYDLDGNGYISKAEMLEIVQAIYKM 131
Cdd:cd15902 134 EYTKLILKEFDANKDGKLELDEMAKLLPVqenfllKFQILGAMDLTKedfekVFEHYDKDNNGVIEGNELDALLKDLLEK 213

                        90       100       110
                ....*....|....*....|....*....|....*..
gi 98985787 132 VSSVMKMPEDestpEKRTEKIFRQMDTNRDGKLSLEE 168
Cdd:cd15902 214 NKADIDKPDL----ENFRDAILRACDKNKDGKIQKTE 246

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 98985787  45 MEEFKKIYGNFFPYGDASKFAEHVFRTFDANGDGTIDFRE----------FIIALSVTSRGKLEQKLKWAFSMYDLDGNG 114
Cdd:cd15902  26 RELLKALNGKDKTDDEVAEKKKEFMEKYDENEDGKIEIRElanilpteenFLLLFRREQPLISSVEFMKIWRKYDTDGSG 105

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 98985787 115 YISKAEMleivQAIYKMVSSVMKMPEDESTPEKRTEKIFRQMDTNRDGKLSLEEFIR 171
Cdd:cd15902 106 FIEAKEL----KGFLKDLLLKNKKHVSPPKLDEYTKLILKEFDANKDGKLELDEMAK 158

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 98985787  34 FLRDcPSGHLSMEEFKKIYgnffpygdasKFAE---HVFRTFDANGDGTIDFREFIIALsvTSRG-KL-EQKLKWAFSMY 108
Cdd:cd16180  46 FDRD-RSGTINFDEFVGLW----------KYIQdwrRLFRRFDRDRSGSIDFNELQNAL--SSFGyRLsPQFVQLLVRKF 112

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 98985787 109 DLDGNGYISKAEMLEIvqaiykmVSSVMKMpedestpekrTEKiFRQMDTNRDG--KLSLEEFI 170
Cdd:cd16180 113 DRRRRGSISFDDFVEA-------CVTLKRL----------TDA-FRKYDTNRTGyaTISYEDFL 158

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985787  27 IQEW---YKGFLRDcPSGHLSMEEFKKIYGNFfPYGDASKFAEHVFRTFDANGDGTIDFREFIIALSVTsrgkleQKLKW 103
Cdd:cd16183  66 ITDWqncFRSFDRD-NSGNIDKNELKQALTSF-GYRLSDQFYDILVRKFDRQGRGTIAFDDFIQCCVVL------QTLTD 137

                        90       100
                ....*....|....*....|....
gi 98985787 104 AFSMYDLDGNGYI--SKAEMLEIV 125
Cdd:cd16183 138 SFRRYDTDQDGWIqiSYEQFLEMV 161

S-100: S-100 domain, which represents the largest family within the superfamily of proteins carrying the Ca-binding EF-hand motif. Note that this S-100 hierarchy contains only S-100 EF-hand domains, other EF-hands have been modeled separately. S100 proteins are expressed exclusively in vertebrates, and are implicated in intracellular and extracellular regulatory activities. Intracellularly, S100 proteins act as Ca-signaling or Ca-buffering proteins. The most unusual characteristic of certain S100 proteins is their occurrence in extracellular space, where they act in a cytokine-like manner through RAGE, the receptor for advanced glycation products. Structural data suggest that many S100 members exist within cells as homo- or heterodimers and even oligomers; oligomerization contributes to their functional diversification. Upon binding calcium, most S100 proteins change conformation to a more open structure exposing a hydrophobic cleft. This hydrophobic surface represents the interaction site of S100 proteins with their target proteins. There is experimental evidence showing that many S100 proteins have multiple binding partners with diverse mode of interaction with different targets. In addition to S100 proteins (such as S100A1,-3,-4,-6,-7,-10,-11,and -13), this group includes the ''fused'' gene family, a group of calcium binding S100-related proteins. The ''fused'' gene family includes multifunctional epidermal differentiation proteins - profilaggrin, trichohyalin, repetin, hornerin, and cornulin; functionally these proteins are associated with keratin intermediate filaments and partially crosslinked to the cell envelope. These ''fused'' gene proteins contain N-terminal sequence with two Ca-binding EF-hands motif, which may be associated with calcium signaling in epidermal cells and autoprocessing in a calcium-dependent manner. In contrast to S100 proteins, "fused" gene family proteins contain an extraordinary high number of almost perfect peptide repeats with regular array of polar and charged residues similar to many known cell envelope proteins.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 98985787 111 DGNGY-ISKAEMLEIVQaiyKMVSSVMKMPEDESTpekrTEKIFRQMDTNRDGKLSLEEFIR 171
Cdd:cd00213  21 EGDKDtLSKKELKELLE---TELPNFLKNQKDPEA----VDKIMKDLDVNKDGKVDFQEFLV 75

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 98985787  40 SGHLSMEEFKKIYGNFFPYGDaSKFAEHVFRTFDANGDGTIDFREFIIAL-SVTSRGKLEQklkwAFSMYDLDGNGYISK 118
Cdd:cd15898  14 DGKLSLKEIKKLLKRLNIRVS-EKELKKLFKEVDTNGDGTLTFDEFEELYkSLTERPELEP----IFKKYAGTNRDYMTL 88

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....
gi 98985787 119 AEMLEIVQAIykmvssvmkmpEDESTPEKRTEKIFRQMDTNRDGK-LSLEEFIR 171
Cdd:cd15898  89 EEFIRFLREE-----------QGENVSEEECEELIEKYEPERENRqLSFEGFTN 131

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 98985787   100 KLKWAFSMYDLDGNGYISKAEMLEIVQAI 128
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKKL 29

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 98985787 105 FSMYDLDGNGYISKAEMLEIVQAIYKmvSSVMKMPEDESTPEKRTEkIFRQMDTNRDGKLSLEEFIRGAKSDPSIVRLLQ 184
Cdd:cd15902   5 WMHFDADGNGYIEGKELDSFLRELLK--ALNGKDKTDDEVAEKKKE-FMEKYDENEDGKIEIRELANILPTEENFLLLFR 81

                ....
gi 98985787 185 CDPS 188
Cdd:cd15902  82 REQP 85

EF hand;

                          10        20
                  ....*....|....*....|..
gi 98985787   150 EKIFRQMDTNRDGKLSLEEFIR 171
Cdd:pfam13202   2 KDTFRQIDLNGDGKISKEELRR 23

Calgranulins: S-100 domain found in proteins belonging to the Calgranulin subgroup of the S100 family of EF-hand calcium-modulated proteins, including S100A8, S100A9, and S100A12 . Note that the S-100 hierarchy, to which this Calgranulin group belongs, contains only S-100 EF-hand domains, other EF-hands have been modeled separately. These proteins are expressed mainly in granulocytes, and are involved in inflammation, allergy, and neuritogenesis, as well as in host-parasite response. Calgranulins are modulated not only by calcium, but also by other metals such as zinc and copper. Structural data suggested that calgranulins may exist in multiple structural forms, homodimers, as well as hetero-oligomers. For example, the S100A8/S100A9 complex called calprotectin plays important roles in the regulation of inflammatory processes, wound repair, and regulating zinc-dependent enzymes as well as microbial growth.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*....
gi 98985787  43 LSMEEFKKIY----GNFFPYGDASKFAEHVFRTFDANGDGTIDFREFII 87
Cdd:cd05030  27 LYKKEFKQLVekelPNFLKKEKNQKAIDKIFEDLDTNQDGQLSFEEFLV 75

EF-hand, calcium binding motif, found in calretinin (CR); CR, also termed 29 kDa calbindin, 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 possibly functions as a calcium buffer, calcium sensor, and apoptosis regulator, which may be implicated in many biological processes, including cell proliferation, differentiation, and cell death. CR contains six EF-hand motifs within two independent domains, CR I-II and CR III-VI. CR I-II consists of EF-hand motifs 1 and 2, and CR III-VI consists of EF-hand motifs 3-6. The first 5 EF-hand motifs are capable of binding calcium ions, while the EF-hand 6 is inactive. Thus, CR has two pairs of cooperative binding sites (I-II and III-IV), which display high affinity calcium-binding sites, and one independent calcium ion-binding site (V), which displays lower affinity binding.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985787  63 KFAEHV---FRTFDANGDGTIDFREFIIALSVTSRGKL--------EQKLKWAFSMYDLDGNGYISKAEMLEIVQAIYKM 131
Cdd:cd16177  43 NFGEKMkefMQKYDKNADGRIEMAELAQILPTEENFLLcfrqhvgsSSEFMEAWRKYDTDRSGYIEANELKGFLSDLLKK 122

                        90       100       110       120
                ....*....|....*....|....*....|....*....|
gi 98985787 132 VSSvmkmPEDESTPEKRTEKIFRQMDTNRDGKLSLEEFIR 171
Cdd:cd16177 123 ANR----PYDEKKLQEYTQTILRMFDLNGDGKLGLSEMAR 158

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 98985787  69 FRTFDANGDGTIDFREFI----------IALSVTSRGKLEQKL----KWAFSMYDLDGNGYISKAEMLEIVQaiykmvss 134
Cdd:cd16227  78 FEEADEDGDGKVTWEEYLadsfgyddedNEEMIKDSTEDDLKLleddKEMFEAADLNKDGKLDKTEFSAFQH-------- 149

                        90       100       110       120
                ....*....|....*....|....*....|....*....|...
gi 98985787 135 vmkmPED-ESTPEKRTEKIFRQMDTNRDGKLSLEEFIRGAKSD 176
Cdd:cd16227 150 ----PEEyPHMHPVLIEQTLRDKDKDNDGFISFQEFLGDRAGH 188

EF-hand domain;

                          10        20
                  ....*....|....*....|....*....
gi 98985787   100 KLKWAFSMYDLDGNGYISKAEMLEIVQAI 128
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSL 29

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 98985787  68 VFRTFDANGDGTID-------FREFIIAL--SVTSRGKLEQKLKWAFSMYDLDGNGYISKAEMLEIV----------QAI 128
Cdd:cd15902   4 VWMHFDADGNGYIEgkeldsfLRELLKALngKDKTDDEVAEKKKEFMEKYDENEDGKIEIRELANILpteenflllfRRE 83

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
gi 98985787 129 YKMVSSVMKMpedestpekrteKIFRQMDTNRDGKLSLEEF 169
Cdd:cd15902  84 QPLISSVEFM------------KIWRKYDTDGSGFIEAKEL 112

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 98985787    150 EKIFRQMDTNRDGKLSLEEFIRGAKS 175
Cdd:smart00054   3 KEAFRLFDKDGDGKIDFEEFKDLLKA 28

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
                ....*....|....*....|....*....|....*....|....*....|
gi 98985787  72 FDANGDGTIDFREFiialsvTSRGKLEQKLKWAFSMYDLDGNGYISKAEM 121
Cdd:cd16183  46 FDRDNSGTINFQEF------AALWKYITDWQNCFRSFDRDNSGNIDKNEL 89

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 98985787  25 HEIQEWYKGFLR---DcPSGHLSMEEFKK-IYGnfFPYGDASKFAEHVFRTFDANGDGTIDFREFI-IALSVtsrgkleQ 99
Cdd:cd16180  64 KYIQDWRRLFRRfdrD-RSGSIDFNELQNaLSS--FGYRLSPQFVQLLVRKFDRRRRGSISFDDFVeACVTL-------K 133

                        90
                ....*....|....*..
gi 98985787 100 KLKWAFSMYDLDGNGYI 116
Cdd:cd16180 134 RLTDAFRKYDTNRTGYA 150

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 98985787 104 AFSMYDLDGNGYISKAEMLEIVQAIYKMVssvmKMPEDESTPEKRTEKIFRQMDTNRDGKLSLEEFIR 171
Cdd:cd16176  90 TWRKYDADHSGFIEADELKSFLKDLLKKA----NKPFDESKLEEYTHTMLKMFDSNNDGKLGLTEMAR 153

S-100: S-100 domain, which represents the largest family within the superfamily of proteins carrying the Ca-binding EF-hand motif. Note that this S-100 hierarchy contains only S-100 EF-hand domains, other EF-hands have been modeled separately. S100 proteins are expressed exclusively in vertebrates, and are implicated in intracellular and extracellular regulatory activities. Intracellularly, S100 proteins act as Ca-signaling or Ca-buffering proteins. The most unusual characteristic of certain S100 proteins is their occurrence in extracellular space, where they act in a cytokine-like manner through RAGE, the receptor for advanced glycation products. Structural data suggest that many S100 members exist within cells as homo- or heterodimers and even oligomers; oligomerization contributes to their functional diversification. Upon binding calcium, most S100 proteins change conformation to a more open structure exposing a hydrophobic cleft. This hydrophobic surface represents the interaction site of S100 proteins with their target proteins. There is experimental evidence showing that many S100 proteins have multiple binding partners with diverse mode of interaction with different targets. In addition to S100 proteins (such as S100A1,-3,-4,-6,-7,-10,-11,and -13), this group includes the ''fused'' gene family, a group of calcium binding S100-related proteins. The ''fused'' gene family includes multifunctional epidermal differentiation proteins - profilaggrin, trichohyalin, repetin, hornerin, and cornulin; functionally these proteins are associated with keratin intermediate filaments and partially crosslinked to the cell envelope. These ''fused'' gene proteins contain N-terminal sequence with two Ca-binding EF-hands motif, which may be associated with calcium signaling in epidermal cells and autoprocessing in a calcium-dependent manner. In contrast to S100 proteins, "fused" gene family proteins contain an extraordinary high number of almost perfect peptide repeats with regular array of polar and charged residues similar to many known cell envelope proteins.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 98985787  36 RDCPSGHLSMEEFKKI----YGNFFPYGDASKFAEHVFRTFDANGDGTIDFREFIIAL 89
Cdd:cd00213  20 KEGDKDTLSKKELKELleteLPNFLKNQKDPEAVDKIMKDLDVNKDGKVDFQEFLVLI 77

Calgranulins: S-100 domain found in proteins belonging to the Calgranulin subgroup of the S100 family of EF-hand calcium-modulated proteins, including S100A8, S100A9, and S100A12 . Note that the S-100 hierarchy, to which this Calgranulin group belongs, contains only S-100 EF-hand domains, other EF-hands have been modeled separately. These proteins are expressed mainly in granulocytes, and are involved in inflammation, allergy, and neuritogenesis, as well as in host-parasite response. Calgranulins are modulated not only by calcium, but also by other metals such as zinc and copper. Structural data suggested that calgranulins may exist in multiple structural forms, homodimers, as well as hetero-oligomers. For example, the S100A8/S100A9 complex called calprotectin plays important roles in the regulation of inflammatory processes, wound repair, and regulating zinc-dependent enzymes as well as microbial growth.

                        10        20
                ....*....|....*....|....*
gi 98985787 146 EKRTEKIFRQMDTNRDGKLSLEEFI 170
Cdd:cd05030  50 QKAIDKIFEDLDTNQDGQLSFEEFL 74

EF hand;

                          10        20
                  ....*....|....*....|
gi 98985787    66 EHVFRTFDANGDGTIDFREF 85
Cdd:pfam13202   2 KDTFRQIDLNGDGKISKEEL 21

serine/threonine protein phosphatase 2A regulatory subunit B"; Heterotrimeric serine/threonine protein phosphatase 2A (PP2A) consists of scaffolding (A), catalytic (C), and variable (B, B', and B") subunits. The variable subunits dictate subcellular localization and substrate specificity of the PP2A holoenzyme. This family includes PP2A regulatory B'' subunits alpha, beta and gamma, encoded by PPP2R3A, PPP2R3B and PPP2R3C, respectively. It also includes subunit delta encoded by PPP2R3D in mouse. These B-family regulatory subunits play various roles including regulation of cytoskeletal assembly, neuronal differentiation, mitogen-activated protein kinase signaling, and apoptosis. Subunits alpha and beta contain two-domain elongated structure with two calcium EF-hands which mediate Ca2+-dependent changes in phosphatase activity.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985787   8 LRPEVMQDLLESTDFTE-HEIQEWYkgflrdcpsghlSMEEFKKIYGNFFP----------------YGDA---SKFAEH 67
Cdd:cd21339  75 RASSFLQDLALLEEEEDiNQETNWF------------SYEHFYVIYCKFWEldtdhdlmiskedlsrYNDAamsNVFIDR 142

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 98985787  68 VF-----RTFDANGDGTIDFREFIIALSVTSRGKLEQKLKWAFSMYDLDGNGYISKAEMleivQAIYKMVSSVMKMPEDE 142
Cdd:cd21339 143 IFsgavtRGKTIQKEGEMSYADFVWFLISEEDKKEPTSIEYWFRCLDIDGDGYLSVFEL----EYFYEEQCERMKIHGIE 218

                       170       180       190
                ....*....|....*....|....*....|
gi 98985787 143 STP-EKRTEKIFRQMDTNRDGKLSLEEFIR 171
Cdd:cd21339 219 PLPfQDVLCQILDLVKPKDPGKITLQDLKR 248