NCBI Conserved Domain Search

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.

Pssm-ID: 320079 [Multi-domain] Cd Length: 261 Bit Score: 444.54 E-value: 3.09e-159

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  40 FMDVWAHYDKDGNGYIEGTELDGFLREFVSSANATDISPEAVTDTMLEELKSCFMEAYDDNQDGKIDIRELAQLLPMEEN 119
Cdd:cd16179   1 FMDVWNHYDTDGNGYIEGTELDGFLREFVSSVNPEDVGPEVVSETALEELKEEFMEAYDENQDGRIDIRELAQLLPTEEN 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 120 FLLLFRFDNPLESSVEFMKIWREYDTDNSGYIEADELKNFLRDLLKEAKKINDVSEDKLIEYTDTMLQVFDANKDGRLQL 199
Cdd:cd16179  81 FLLLFRRDNPLDSSVEFMKVWREYDKDNSGYIEADELKNFLKHLLKEAKRDNDVSEDKLIEYTDTILQLFDRNKDGKLQL 160

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 200 SEMAKLLPVKENFLCRQVFKGATKLTKEDIEKVFSLYDRDNSGTIENEELKGFLKDLLELVKKdDYDAQDLAAFEETIMR 279
Cdd:cd16179 161 SEMARLLPVKENFLCRPIFKGAGKLTREDIDRVFALYDRDNNGTIENEELTGFLKDLLELVQE-DYDEQDLEEFKEIILR 239

                       250       260
                ....*....|....*....|..
gi 17136674 280 GVGTDKHGKISRKELTMILLTL 301
Cdd:cd16179 240 GWDFNNDGKISRKELTMLLLQL 261

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.

Pssm-ID: 320075 [Multi-domain] Cd Length: 254 Bit Score: 321.22 E-value: 1.12e-110

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  40 FMDVWAHYDKDGNGYIEGTELDGFLREFVSSANATDIspeavTDTMLEELKSCFMEAYDDNQDGKIDIRELAQLLPMEEN 119
Cdd:cd15902   1 FMEVWMHFDADGNGYIEGKELDSFLRELLKALNGKDK-----TDDEVAEKKKEFMEKYDENEDGKIEIRELANILPTEEN 75

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 120 FLLLFRFDNPLESSVEFMKIWREYDTDNSGYIEADELKNFLRDLLKEAKKIndVSEDKLIEYTDTMLQVFDANKDGRLQL 199
Cdd:cd15902  76 FLLLFRREQPLISSVEFMKIWRKYDTDGSGFIEAKELKGFLKDLLLKNKKH--VSPPKLDEYTKLILKEFDANKDGKLEL 153

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 200 SEMAKLLPVKENFLCRQVFKGATKLTKEDIEKVFSLYDRDNSGTIENEELKGFLKDLLELVKKDDyDAQDLAAFEETIMR 279
Cdd:cd15902 154 DEMAKLLPVQENFLLKFQILGAMDLTKEDFEKVFEHYDKDNNGVIEGNELDALLKDLLEKNKADI-DKPDLENFRDAILR 232

                       250       260
                ....*....|....*....|.
gi 17136674 280 GVGTDKHGKISRKELTMILLT 300
Cdd:cd15902 233 ACDKNKDGKIQKTELALFLSA 253

EF-hand, calcium binding motif, found in secretagogin (SCGN); 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 calcium sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. It also serves as a calcium buffer in neurons. Thus, SCGN may be linked to the pathogenesis of neurological diseases such as Alzheimer's, and also acts as a serum marker of neuronal damage, or as a tumor biomarker. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. All six EF hand motifs of SCGN in some eukaryotes, including D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, could potentially bind six calcium ions. In contrast, SCGNs from higher eukaryotes have at least one non-functional EF-hand motif due to the mutation(s) or deletions. For instance, the EF1 loop does not coordinate calcium ion due to the key residue asparagine replaced by lysine in SCGNs of many mammalian species. Moreover, the EF2 loop seems to be competent for calcium-binding in most mammalian SCGNs except for human and chimpanzee orthologs.

Pssm-ID: 320078 [Multi-domain] Cd Length: 257 Bit Score: 253.48 E-value: 6.45e-84

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  40 FMDVWAHYDKDGNGYIEGTELDGFLREFVSSANATDIspeaVTDTMLEELKSCFMEAYDDNQDGKIDIRELAQ-LLPMEE 118
Cdd:cd16178   1 FAEIWQHFDADESGYIEGKELDNFFKDLLKKLGTKDT----ISADEVQDVKECFMSAYDVTGDGRIQIQELANiILPDDE 76

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 119 NFLLLFRFDNPLESSVEFMKIWREYDTDNSGYIEADELKNFLRDLLKEAKKIndVSEDKLIEYTDTMLQVFDANKDGRLQ 198
Cdd:cd16178  77 NFLLFFRREEPLDSSVEFMRIWRKYDADSSGYISAAELKNFLRDLFLQHKKV--ITEDKLDEYTDTMMKIFDKNKDGRLD 154

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 199 LSEMAKLLPVKENFLCR-QVFKGATKLTKEDIEKVFSLYDRDNSGTIENEELKGFLKDLLELVKKDDyDAQDLAAFEETI 277
Cdd:cd16178 155 LNDMARILALQENFLLQfKMDAMSEEERKRDFEKIFAHYDVSKTGALEGPEVDGFVKDMMELVKPSI-SGVQLDKFKEII 233

                       250       260
                ....*....|....*....|.
gi 17136674 278 MRGVGTDKHGKISRKELTMIL 298
Cdd:cd16178 234 LNHCDVNKDGKIQKSELALCL 254

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.

Pssm-ID: 320077 [Multi-domain] Cd Length: 248 Bit Score: 229.76 E-value: 9.29e-75

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  40 FMDVWAHYDKDGNGYIEGTELDGFLREFVSSANATDISPEAVTdtmLEELKSCFMEAYDDNQDGKIDIRELAQLLPMEEN 119
Cdd:cd16177   1 FLEIWKHFDADGNGYIEGKELENFFRELERARRGAGVDSKSAN---FGEKMKEFMQKYDKNADGRIEMAELAQILPTEEN 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 120 FLLLFRfdNPLESSVEFMKIWREYDTDNSGYIEADELKNFLRDLLKEAKKINDvsEDKLIEYTDTMLQVFDANKDGRLQL 199
Cdd:cd16177  78 FLLCFR--QHVGSSSEFMEAWRKYDTDRSGYIEANELKGFLSDLLKKANRPYD--EKKLQEYTQTILRMFDLNGDGKLGL 153

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 200 SEMAKLLPVKENFLCRqvFKGaTKLTKEDIEKVFSLYDRDNSGTIENEELKGFLKDLLELVKKdDYDAQDLAAFEETIMr 279
Cdd:cd16177 154 SEMARLLPVQENFLLK--FQG-MKLSSEEFNAIFAFYDKDGSGYIDENELDALLKDLYEKNKK-EMDIQQLTNYKKSIM- 228

                       250       260
                ....*....|....*....|.
gi 17136674 280 gvGTDKHGKISRKELTMILLT 300
Cdd:cd16177 229 --SLSDGGKLYRKELEMVLCS 247

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.

Pssm-ID: 320076 [Multi-domain] Cd Length: 243 Bit Score: 224.33 E-value: 9.97e-73

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  40 FMDVWAHYDKDGNGYIEGTELDGFLREFVSSANAT--DISPEAVTdtmleelkscFMEAYDDNQDGKIDIRELAQLLPME 117
Cdd:cd16176   1 FLEIWHHYDNDGNGYIEGKELQSFIQELQQARKKAglELSDQMKA----------FVDQYGQSTDGKIGIVELAQILPTE 70

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 118 ENFLLLFRfdNPLESSVEFMKIWREYDTDNSGYIEADELKNFLRDLLKEAKKinDVSEDKLIEYTDTMLQVFDANKDGRL 197
Cdd:cd16176  71 ENFLLFFR--QQLKSSEEFMQTWRKYDADHSGFIEADELKSFLKDLLKKANK--PFDESKLEEYTHTMLKMFDSNNDGKL 146

                       170       180       190       200       210       220       230       240
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 198 QLSEMAKLLPVKENFLCRqvFKGaTKLTKEDIEKVFSLYDRDNSGTIENEELKGFLKDLLELVKKdDYDAQDLAAFEETI 277
Cdd:cd16176 147 GLTEMARLLPVQENFLLK--FQG-VKMCGKEFNKIFELYDQDGNGYIDENELDALLKDLCEKNKK-DLDINNISTYKKSI 222

                       250       260
                ....*....|....*....|.
gi 17136674 278 MrgvGTDKHGKISRKELTMIL 298
Cdd:cd16176 223 M---ALSDGGKLYRTELALIL 240

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.

Pssm-ID: 238008 [Multi-domain] Cd Length: 63 Bit Score: 56.02 E-value: 1.50e-10

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 17136674 135 EFMKIWREYDTDNSGYIEADELKNFLRDLlkeakkindvSEDKLIEYTDTMLQVFDANKDGRLQLSEMAKLL 206
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSL----------GEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

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.

Pssm-ID: 320075 [Multi-domain] Cd Length: 254 Bit Score: 56.98 E-value: 2.56e-09

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  19 NFMRQYRDPESRELKKlsaNQFMDVWAHYDKDGNGYIEGTELDGFLREFVSSANATDISPEavtdtmLEELKSCFMEAYD 98
Cdd:cd15902 165 NFLLKFQILGAMDLTK---EDFEKVFEHYDKDNNGVIEGNELDALLKDLLEKNKADIDKPD------LENFRDAILRACD 235

                        90
                ....*....|....*.
gi 17136674  99 DNQDGKIDIRELAQLL 114
Cdd:cd15902 236 KNKDGKIQKTELALFL 251

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.

Pssm-ID: 238008 [Multi-domain] Cd Length: 63 Bit Score: 50.62 E-value: 1.39e-08

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 17136674 228 DIEKVFSLYDRDNSGTIENEELKGFLKDLLELVKKDDydaqdlaafEETIMRGVGTDKHGKISRKELTMIL 298
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSLGEGLSEEE---------IDEMIREVDKDGDGKIDFEEFLELM 62

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

Pssm-ID: 444056 [Multi-domain] Cd Length: 137 Bit Score: 52.49 E-value: 1.51e-08

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  40 FMDVWAHYDKDGNGYIEGTELdgflrefvssanatdispEAVTDTMLEELkscfMEAYDDNQDGKIDIRELAQLlpMEEN 119
Cdd:COG5126   7 LDRRFDLLDADGDGVLERDDF------------------EALFRRLWATL----FSEADTDGDGRISREEFVAG--MESL 62

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 120 FLLLFRfdnplessVEFMKIWREYDTDNSGYIEADELKNFLRDLlkeakkinDVSEDKLieytDTMLQVFDANKDGRLQL 199
Cdd:COG5126  63 FEATVE--------PFARAAFDLLDTDGDGKISADEFRRLLTAL--------GVSEEEA----DELFARLDTDGDGKISF 122


                ....*..
gi 17136674 200 SEMAKLL 206
Cdd:COG5126 123 EEFVAAV 129

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.

Pssm-ID: 238008 [Multi-domain] Cd Length: 63 Bit Score: 47.54 E-value: 1.49e-07

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 17136674  39 QFMDVWAHYDKDGNGYIEGTELDGFLREFvssanatdispeavTDTMLEELKSCFMEAYDDNQDGKIDIRELAQLL 114
Cdd:cd00051   1 ELREAFRLFDKDGDGTISADELKAALKSL--------------GEGLSEEEIDEMIREVDKDGDGKIDFEEFLELM 62

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

Pssm-ID: 444056 [Multi-domain] Cd Length: 137 Bit Score: 49.41 E-value: 1.86e-07

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 136 FMKIWREYDTDNSGYIEADELKNFLRDLLkeakkindvsedklieytDTMLQVFDANKDGRLQLSEMAKLLPvkenflcr 215
Cdd:COG5126   7 LDRRFDLLDADGDGVLERDDFEALFRRLW------------------ATLFSEADTDGDGRISREEFVAGME-------- 60

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 17136674 216 qvfKGATKLTKEDIEKVFSLYDRDNSGTIENEELKGFLKDLlelvkkdDYDAQDLAAfeetIMRGVGTDKHGKISRKEL 294
Cdd:COG5126  61 ---SLFEATVEPFARAAFDLLDTDGDGKISADEFRRLLTAL-------GVSEEEADE----LFARLDTDGDGKISFEEF 125

EF-hand, calcium binding motif, found in beta-parvalbumin; Beta-parvalbumin, also termed Oncomodulin-1 (OM), is a small calcium-binding protein that is expressed in hepatomas, as well as in the blastocyst and the cytotrophoblasts of the placenta. It is also found to be expressed in the cochlear outer hair cells of the organ of Corti and frequently expressed in neoplasms. Mammalian beta-parvalbumin is secreted by activated macrophages and neutrophils. It may function as a tissue-specific Ca2+-dependent regulatory protein, and may also serve as a specialized cytosolic Ca2+ buffer. Beta-parvalbumin acts as a potent growth-promoting signal between the innate immune system and neurons in vivo. It has high and specific affinity for its receptor on retinal ganglion cells (RGC) and functions as the principal mediator of optic nerve regeneration. It exerts its effects in a cyclic adenosine monophosphate (cAMP)-dependent manner and can further elevate intracellular cAMP levels. Moreover, beta-parvalbumin is associated with efferent function and outer hair cell electromotility, and can identify different hair cell types in the mammalian inner ear. Beta-parvalbumin is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. The EF site displays a high-affinity for Ca2+/Mg2+, and the CD site is a low-affinity Ca2+-specific site. In addition, beta-parvalbumin is distinguished from other parvalbumins by its unusually low isoelectric point (pI = 3.1) and sequence eccentricities (e.g., Y57-L58-D59 instead of F57-I58-E59).

Pssm-ID: 319998 [Multi-domain] Cd Length: 101 Bit Score: 46.26 E-value: 1.22e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  32 LKKLSANQFMDVWAHYDKDGNGYIEGTELDGFLREFVSSAnatdispEAVTDTmleELKScFMEAYDDNQDGKIDIRELA 111
Cdd:cd16255  28 LSKKSADDVKKVFEIIDQDKSGFIEEEELKLFLQNFSSGA-------RELTDA---ETKA-FLKAGDSDGDGKIGVEEFQ 96


                ..
gi 17136674 112 QL 113
Cdd:cd16255  97 AL 98

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+.

Pssm-ID: 320055 [Multi-domain] Cd Length: 164 Bit Score: 47.14 E-value: 1.58e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 135 EFMKIWREYDTDNSGYIEADELKNFLrdllkeakkINDVSEDKLIEYTDTMLQVFDANKDGRLQLSEMAKLLpvkeNFLc 214
Cdd:cd16180   1 ELRRIFQAVDRDRSGRISAKELQRAL---------SNGDWTPFSIETVRLMINMFDRDRSGTINFDEFVGLW----KYI- 66

                        90       100       110
                ....*....|....*....|....*....|....*.
gi 17136674 215 rqvfkgatkltkEDIEKVFSLYDRDNSGTIENEELK 250
Cdd:cd16180  67 ------------QDWRRLFRRFDRDRSGSIDFNELQ 90

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

Pssm-ID: 320059 [Multi-domain] Cd Length: 165 Bit Score: 45.72 E-value: 4.92e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 144 DTDNSGYIEADELKNFLRDllKEAKKINDvsedkliEYTDTMLQVFDANKDGRLQLSEMAKLLpvkeNFLcrQVFKGatk 223
Cdd:cd16184  10 DRDRSGKISAKELQQALVN--GNWSHFND-------ETCRLMIGMFDKDKSGTIDIYEFQALW----NYI--QQWKQ--- 71

                        90       100
                ....*....|....*....|....*.
gi 17136674 224 ltkediekVFSLYDRDNSGTIENEEL 249
Cdd:cd16184  72 --------VFQQFDRDRSGSIDENEL 89

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

Pssm-ID: 319994 [Multi-domain] Cd Length: 101 Bit Score: 43.68 E-value: 8.18e-06

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 17136674 220 GATKLTKEDIEKVFSLYDRDNSGTIENEELKGFLKDLlelvkkdDYDAQDLAAFEETIMRGVG-TDKHGKISRKEL 294
Cdd:cd16251  27 GLKQKSEDQIKKVFQILDKDKSGFIEEEELKYILKGF-------SIAGRDLTDEETKALLAAGdTDGDGKIGVEEF 95

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.

Pssm-ID: 320075 [Multi-domain] Cd Length: 254 Bit Score: 46.19 E-value: 8.40e-06

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 17136674 231 KVFSLYDRDNSGTIENEELKGFLKDLLELVKKDDYDAQDLAAFEETIMRGVGTDKHGKISRKELTMILLTL 301
Cdd:cd15902   3 EVWMHFDADGNGYIEGKELDSFLRELLKALNGKDKTDDEVAEKKKEFMEKYDENEDGKIEIRELANILPTE 73

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+.

Pssm-ID: 320055 [Multi-domain] Cd Length: 164 Bit Score: 44.83 E-value: 9.98e-06

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  48 DKDGNGYIEGTELDGFLrefvSSANATDISPEAVtDTMLeelkscFMeaYDDNQDGKIDIRELAQLLpmeeNFLLlfrfd 127
Cdd:cd16180  10 DRDRSGRISAKELQRAL----SNGDWTPFSIETV-RLMI------NM--FDRDRSGTINFDEFVGLW----KYIQ----- 67

                        90       100       110
                ....*....|....*....|....*....|....*.
gi 17136674 128 nplessvEFMKIWREYDTDNSGYIEADELKNFLRDL 163
Cdd:cd16180  68 -------DWRRLFRRFDRDRSGSIDFNELQNALSSF 96

EF-hand domain pair;

Pssm-ID: 463900 [Multi-domain] Cd Length: 67 Bit Score: 42.24 E-value: 1.24e-05

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674   137 MKIWREYDTDNSGYIEADELKNFLRDLLKEakkiNDVSEDKLieytDTMLQVFDANKDGRLQLSEMAKLL 206
Cdd:pfam13499   5 KEAFKLLDSDGDGYLDVEELKKLLRKLEEG----EPLSDEEV----EELFKEFDLDKDGRISFEEFLELY 66

centrin; Provisional

Pssm-ID: 185503 [Multi-domain] Cd Length: 158 Bit Score: 44.29 E-value: 1.49e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  143 YDTDNSGYIEADELKNFLRDLLKEAKKindvsedkliEYTDTMLQVFDANKDGRLQLSEMAKLLPVKEnflcrqvfkgAT 222
Cdd:PTZ00183  26 FDTDGSGTIDPKELKVAMRSLGFEPKK----------EEIKQMIADVDKDGSGKIDFEEFLDIMTKKL----------GE 85

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 17136674  223 KLTKEDIEKVFSLYDRDNSGTIENEELKGFLKDLLE 258
Cdd:PTZ00183  86 RDPREEILKAFRLFDDDKTGKISLKNLKRVAKELGE 121

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.

Pssm-ID: 320058 [Multi-domain] Cd Length: 165 Bit Score: 44.55 E-value: 1.60e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  48 DKDGNGYIEGTELdgflREFVSSANATDISPEAVtdtmleelkSCFMEAYDDNQDGKIDIRElaqllpmeenFLLLFRFD 127
Cdd:cd16183  10 DKDRSGQISATEL----QQALSNGTWTPFNPETV---------RLMIGMFDRDNSGTINFQE----------FAALWKYI 66

                        90       100       110
                ....*....|....*....|....*....|....
gi 17136674 128 NplessvEFMKIWREYDTDNSGYIEADELKNFLR 161
Cdd:cd16183  67 T------DWQNCFRSFDRDNSGNIDKNELKQALT 94

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+.

Pssm-ID: 320054 [Multi-domain] Cd Length: 165 Bit Score: 43.96 E-value: 2.06e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 135 EFMKIWREYDTDnSGYIEADELKNFLRDLLkeakkINDVSEDKLIEYTDTMLQVFDANKDGRLQLSEmakllpvkenflc 214
Cdd:cd15897   1 QLRNVFQAVAGD-DGEISATELQQALSNVG-----WTHFDLGFSLETCRSMIAMMDRDHSGKLNFSE------------- 61

                        90       100       110       120
                ....*....|....*....|....*....|....*....|.
gi 17136674 215 rqvFKGATKLTKeDIEKVFSLYDRDNSGTIENEELKGFLKD 255
Cdd:cd15897  62 ---FKGLWNYIK-AWQEIFRTYDTDGSGTIDSNELRQALSG 98

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

Pssm-ID: 319994 [Multi-domain] Cd Length: 101 Bit Score: 42.52 E-value: 2.37e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  32 LKKLSANQFMDVWAHYDKDGNGYIEGTELDGFLREFvsSANATDISPeavtdtmlEELKScFMEAYDDNQDGKIDIRELA 111
Cdd:cd16251  28 LKQKSEDQIKKVFQILDKDKSGFIEEEELKYILKGF--SIAGRDLTD--------EETKA-LLAAGDTDGDGKIGVEEFA 96


                ..
gi 17136674 112 QL 113
Cdd:cd16251  97 TL 98

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.

Pssm-ID: 320079 [Multi-domain] Cd Length: 261 Bit Score: 44.71 E-value: 2.80e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  33 KKLSANQFMDVWAHYDKDGNGYIEGTELDGFLREFVssanatDISPEAVTDTMLEELKSCFMEAYDDNQDGKIDIRELAQ 112
Cdd:cd16179 183 GKLTREDIDRVFALYDRDNNGTIENEELTGFLKDLL------ELVQEDYDEQDLEEFKEIILRGWDFNNDGKISRKELTM 256


                ..
gi 17136674 113 LL 114
Cdd:cd16179 257 LL 258

EF-hand, calcium binding motif, found in alpha-parvalbumin; Alpha-parvalbumin is cytosolic Ca2+/Mg2+-binding protein expressed mainly in fast-twitch skeletal myofibrils, where it may act as a soluble relaxing factor facilitating the Ca2+-mediated relaxation phase. It is also expressed in rapidly firing neurons, particularly GABA-ergic neurons, and thus may confer protection against Ca2+ toxicity. The major role of alpha-parvalbumin is metal buffering and transport of Ca2+. It binds different metal cations, and exhibits very high affinity for Ca2+ and physiologically significant affinity for Mg2+. Alpha-parvalbumin is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Both metal ion-binding sites in alpha-parvalbumin are high-affinity sites. Additionally, in contrast to beta-parvalbumin, alpha-parvalbumin is less acidic and has an additional residue in the C-terminal helix.

Pssm-ID: 319997 [Multi-domain] Cd Length: 101 Bit Score: 41.73 E-value: 4.35e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  32 LKKLSANQFMDVWAHYDKDGNGYIEGTELDGFLREFvsSANATDISPeavtdtmlEELKScFMEAYDDNQDGKIDIRELA 111
Cdd:cd16254  28 LKKKSADDVKKVFHILDKDKSGFIEEDELKFVLKGF--SPDGRDLSD--------KETKA-LLAAGDKDGDGKIGIDEFA 96


                ...
gi 17136674 112 QLL 114
Cdd:cd16254  97 TLV 99

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.

Pssm-ID: 238008 [Multi-domain] Cd Length: 63 Bit Score: 40.22 E-value: 6.76e-05

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 185 MLQVFDANKDGRLQLSEMAKLLPVKEnflcrqvfkgaTKLTKEDIEKVFSLYDRDNSGTIENEELKGFLK 254
Cdd:cd00051   5 AFRLFDKDGDGTISADELKAALKSLG-----------EGLSEEEIDEMIREVDKDGDGKIDFEEFLELMA 63

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

Pssm-ID: 319996 [Multi-domain] Cd Length: 101 Bit Score: 41.39 E-value: 6.92e-05

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 17136674 220 GATKLTKEDIEKVFSLYDRDNSGTIENEELKGFLKDLLElvkkddyDAQDLAAFEETIMRGVG-TDKHGKISRKE 293
Cdd:cd16253  27 GLSKKSPADIKKVFNILDQDKSGFIEEEELKLFLKNFSD-------GARVLSDKETKNFLAAGdSDGDGKIGVDE 94

XopAW family type III secretion system calcium-binding effector;

Pssm-ID: 469301 [Multi-domain] Cd Length: 227 Bit Score: 43.13 E-value: 7.30e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  144 DTDNSGYIEADELKNFLrdllkeakkiNDVSEDKLIEYTDTMLQVFDANKDGRLQLSEMAKLLPVKENflcRQVFKGATK 223
Cdd:NF041410  37 DSDGDGSVSQDELSSAL----------SSKSDDGSLIDLSELFSDLDSDGDGSLSSDELAAAAPPPPP---PPDQAPSTE 103

                         90       100
                 ....*....|....*....|....*.
gi 17136674  224 LTKEdiekVFSLYDRDNSGTIENEEL 249
Cdd:NF041410 104 LADD----LLSALDTDGDGSISSDEL 125

EF-hand, calcium binding motif, found in beta-parvalbumin; Beta-parvalbumin, also termed Oncomodulin-1 (OM), is a small calcium-binding protein that is expressed in hepatomas, as well as in the blastocyst and the cytotrophoblasts of the placenta. It is also found to be expressed in the cochlear outer hair cells of the organ of Corti and frequently expressed in neoplasms. Mammalian beta-parvalbumin is secreted by activated macrophages and neutrophils. It may function as a tissue-specific Ca2+-dependent regulatory protein, and may also serve as a specialized cytosolic Ca2+ buffer. Beta-parvalbumin acts as a potent growth-promoting signal between the innate immune system and neurons in vivo. It has high and specific affinity for its receptor on retinal ganglion cells (RGC) and functions as the principal mediator of optic nerve regeneration. It exerts its effects in a cyclic adenosine monophosphate (cAMP)-dependent manner and can further elevate intracellular cAMP levels. Moreover, beta-parvalbumin is associated with efferent function and outer hair cell electromotility, and can identify different hair cell types in the mammalian inner ear. Beta-parvalbumin is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. The EF site displays a high-affinity for Ca2+/Mg2+, and the CD site is a low-affinity Ca2+-specific site. In addition, beta-parvalbumin is distinguished from other parvalbumins by its unusually low isoelectric point (pI = 3.1) and sequence eccentricities (e.g., Y57-L58-D59 instead of F57-I58-E59).

Pssm-ID: 319998 [Multi-domain] Cd Length: 101 Bit Score: 40.87 E-value: 8.90e-05

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 17136674 220 GATKLTKEDIEKVFSLYDRDNSGTIENEELKGFLKDLlelvkkdDYDAQDLAAFE-ETIMRGVGTDKHGKISRKE 293
Cdd:cd16255  27 GLSKKSADDVKKVFEIIDQDKSGFIEEEELKLFLQNF-------SSGARELTDAEtKAFLKAGDSDGDGKIGVEE 94

EF-hand, calcium binding motif, found in alpha-parvalbumin; Alpha-parvalbumin is cytosolic Ca2+/Mg2+-binding protein expressed mainly in fast-twitch skeletal myofibrils, where it may act as a soluble relaxing factor facilitating the Ca2+-mediated relaxation phase. It is also expressed in rapidly firing neurons, particularly GABA-ergic neurons, and thus may confer protection against Ca2+ toxicity. The major role of alpha-parvalbumin is metal buffering and transport of Ca2+. It binds different metal cations, and exhibits very high affinity for Ca2+ and physiologically significant affinity for Mg2+. Alpha-parvalbumin is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Both metal ion-binding sites in alpha-parvalbumin are high-affinity sites. Additionally, in contrast to beta-parvalbumin, alpha-parvalbumin is less acidic and has an additional residue in the C-terminal helix.

Pssm-ID: 319997 [Multi-domain] Cd Length: 101 Bit Score: 40.96 E-value: 9.29e-05

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 220 GATKLTKEDIEKVFSLYDRDNSGTIENEELKGFLKDLlelvkkdDYDAQDLAAFEETIMRGVG-TDKHGKISRKELTMIL 298
Cdd:cd16254  27 GLKKKSADDVKKVFHILDKDKSGFIEEDELKFVLKGF-------SPDGRDLSDKETKALLAAGdKDGDGKIGIDEFATLV 99

EF-hand domain pair;

Pssm-ID: 463900 [Multi-domain] Cd Length: 67 Bit Score: 38.77 E-value: 2.43e-04

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 17136674   226 KEDIEKVFSLYDRDNSGTIENEELKGFLKDLLELVKKDDYDAQDlaafeetIMRGVGTDKHGKISRKE 293
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEPLSDEEVEE-------LFKEFDLDKDGRISFEE 61

EF-hand, calcium binding motif, found in beta-parvalbumin; Beta-parvalbumin, also termed Oncomodulin-1 (OM), is a small calcium-binding protein that is expressed in hepatomas, as well as in the blastocyst and the cytotrophoblasts of the placenta. It is also found to be expressed in the cochlear outer hair cells of the organ of Corti and frequently expressed in neoplasms. Mammalian beta-parvalbumin is secreted by activated macrophages and neutrophils. It may function as a tissue-specific Ca2+-dependent regulatory protein, and may also serve as a specialized cytosolic Ca2+ buffer. Beta-parvalbumin acts as a potent growth-promoting signal between the innate immune system and neurons in vivo. It has high and specific affinity for its receptor on retinal ganglion cells (RGC) and functions as the principal mediator of optic nerve regeneration. It exerts its effects in a cyclic adenosine monophosphate (cAMP)-dependent manner and can further elevate intracellular cAMP levels. Moreover, beta-parvalbumin is associated with efferent function and outer hair cell electromotility, and can identify different hair cell types in the mammalian inner ear. Beta-parvalbumin is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. The EF site displays a high-affinity for Ca2+/Mg2+, and the CD site is a low-affinity Ca2+-specific site. In addition, beta-parvalbumin is distinguished from other parvalbumins by its unusually low isoelectric point (pI = 3.1) and sequence eccentricities (e.g., Y57-L58-D59 instead of F57-I58-E59).

Pssm-ID: 319998 [Multi-domain] Cd Length: 101 Bit Score: 39.71 E-value: 2.50e-04

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 17136674 132 SSVEFMKIWREYDTDNSGYIEADELKNFLRDLLKEAKKINDvSEdklieyTDTMLQVFDANKDGRLQLSEMAKL 205
Cdd:cd16255  32 SADDVKKVFEIIDQDKSGFIEEEELKLFLQNFSSGARELTD-AE------TKAFLKAGDSDGDGKIGVEEFQAL 98

calmodulin; Provisional

Pssm-ID: 185504 [Multi-domain] Cd Length: 149 Bit Score: 40.13 E-value: 3.92e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674   39 QFMDVWAHYDKDGNGYIEGTELDGFLREFvsSANATdispEAVTDTMLEELkscfmeayDDNQDGKIDIRELAQLL--PM 116
Cdd:PTZ00184  12 EFKEAFSLFDKDGDGTITTKELGTVMRSL--GQNPT----EAELQDMINEV--------DADGNGTIDFPEFLTLMarKM 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  117 EENflllfrfdnplESSVEFMKIWREYDTDNSGYIEADELKNFLRDLlkeAKKINDvsedkliEYTDTMLQVFDANKDGR 196
Cdd:PTZ00184  78 KDT-----------DSEEEIKEAFKVFDRDGNGFISAAELRHVMTNL---GEKLTD-------EEVDEMIREADVDGDGQ 136

                        170
                 ....*....|...
gi 17136674  197 LQLSEMAKLLPVK 209
Cdd:PTZ00184 137 INYEEFVKMMMSK 149

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.

Pssm-ID: 197492 [Multi-domain] Cd Length: 29 Bit Score: 36.97 E-value: 4.10e-04

                           10        20
                   ....*....|....*....|....*....
gi 17136674    135 EFMKIWREYDTDNSGYIEADELKNFLRDL 163
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLKAL 29

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

Pssm-ID: 319994 [Multi-domain] Cd Length: 101 Bit Score: 39.05 E-value: 4.36e-04

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 17136674 138 KIWREYDTDNSGYIEADELKNFLRDLLKEAKKINDvsedkliEYTDTMLQVFDANKDGRLQLSEMAKL 205
Cdd:cd16251  38 KVFQILDKDKSGFIEEEELKYILKGFSIAGRDLTD-------EETKALLAAGDTDGDGKIGVEEFATL 98

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.

Pssm-ID: 425435 [Multi-domain] Cd Length: 29 Bit Score: 36.61 E-value: 5.01e-04

                          10        20
                  ....*....|....*....|....*....
gi 17136674   135 EFMKIWREYDTDNSGYIEADELKNFLRDL 163
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKKL 29

EF-hand domain;

Pssm-ID: 463869 [Multi-domain] Cd Length: 30 Bit Score: 36.77 E-value: 5.27e-04

                          10        20
                  ....*....|....*....|....*....
gi 17136674   135 EFMKIWREYDTDNSGYIEADELKNFLRDL 163
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSL 29

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

Pssm-ID: 319996 [Multi-domain] Cd Length: 101 Bit Score: 38.31 E-value: 7.24e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  32 LKKLSANQFMDVWAHYDKDGNGYIEGTELDGFLREFvsSANATDISPEAVtdtmleelkSCFMEAYDDNQDGKIDIRELA 111
Cdd:cd16253  28 LSKKSPADIKKVFNILDQDKSGFIEEEELKLFLKNF--SDGARVLSDKET---------KNFLAAGDSDGDGKIGVDEFK 96


                ....*
gi 17136674 112 QLLPM 116
Cdd:cd16253  97 SMVKA 101

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.

Pssm-ID: 320077 [Multi-domain] Cd Length: 248 Bit Score: 40.24 E-value: 7.26e-04

                        10        20        30
                ....*....|....*....|....*....|....
gi 17136674  34 KLSANQFMDVWAHYDKDGNGYIEGTELDGFLREF 67
Cdd:cd16177 174 KLSSEEFNAIFAFYDKDGSGYIDENELDALLKDL 207

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.

Pssm-ID: 320029 [Multi-domain] Cd Length: 137 Bit Score: 38.80 E-value: 9.47e-04

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 136 FMKIWREYDTDNSGYIEADELKNFLRDLLKEAKKindvsedkliEYTDTMLQVFDANKDGRLQLSEMAKLLpvkeNFLCR 215
Cdd:cd15898   2 LRRQWIKADKDGDGKLSLKEIKKLLKRLNIRVSE----------KELKKLFKEVDTNGDGTLTFDEFEELY----KSLTE 67

                        90       100       110       120
                ....*....|....*....|....*....|....*....|
gi 17136674 216 QvfkgatkltkEDIEKVFSLYDRDNSGTIENEELKGFLKD 255
Cdd:cd15898  68 R----------PELEPIFKKYAGTNRDYMTLEEFIRFLRE 97

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.

Pssm-ID: 320058 [Multi-domain] Cd Length: 165 Bit Score: 38.77 E-value: 1.25e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 144 DTDNSGYIEADELKNFLRDllKEAKKINDvsedkliEYTDTMLQVFDANKDGRLQLSEMAKLlpvkenflcrqvFKGATk 223
Cdd:cd16183  10 DKDRSGQISATELQQALSN--GTWTPFNP-------ETVRLMIGMFDRDNSGTINFQEFAAL------------WKYIT- 67

                        90       100
                ....*....|....*....|....*..
gi 17136674 224 ltkeDIEKVFSLYDRDNSGTIENEELK 250
Cdd:cd16183  68 ----DWQNCFRSFDRDNSGNIDKNELK 90

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

Pssm-ID: 319996 [Multi-domain] Cd Length: 101 Bit Score: 37.54 E-value: 1.45e-03

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 17136674 131 ESSVEFMKIWREYDTDNSGYIEADELKNFLRDLLKEAKKINDVSedklieyTDTMLQVFDANKDGRLQLSEMAKL 205
Cdd:cd16253  31 KSPADIKKVFNILDQDKSGFIEEEELKLFLKNFSDGARVLSDKE-------TKNFLAAGDSDGDGKIGVDEFKSM 98

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.

Pssm-ID: 320029 [Multi-domain] Cd Length: 137 Bit Score: 37.65 E-value: 2.37e-03

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 17136674  89 LKSCFMEAyDDNQDGKIDIRELAQLLpmeenflllfRFDNPLESSVEFMKIWREYDTDNSGYIEADELKNFLRDLL 164
Cdd:cd15898   2 LRRQWIKA-DKDGDGKLSLKEIKKLL----------KRLNIRVSEKELKKLFKEVDTNGDGTLTFDEFEELYKSLT 66

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.

Pssm-ID: 320029 [Multi-domain] Cd Length: 137 Bit Score: 37.26 E-value: 2.69e-03

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 189 FDANKDGRLQLSEMAKLLpVKENFlcrqvfkgatKLTKEDIEKVFSLYDRDNSGTIENEELKGFLKDLLE 258
Cdd:cd15898   9 ADKDGDGKLSLKEIKKLL-KRLNI----------RVSEKELKKLFKEVDTNGDGTLTFDEFEELYKSLTE 67

Penta-EF hand, calcium binding motifs, found in calpain-12 (CAPN12); CAPN12, also termed calcium-activated neutral proteinase 12 (CANP 12), is a calpain large subunit mainly expressed in the cortex of the hair follicle. It may affect apoptosis regulation. CAPN12 contains a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2+-binding penta-EF-hand (PEF) domain.

Pssm-ID: 320069 [Multi-domain] Cd Length: 169 Bit Score: 37.93 E-value: 2.82e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 151 IEADELKNFLRDLLkeAKKINDVSEDKLIEYTDTMLQVFDANKDGRLQLSEMAKLLpvkenflcrqvfkgaTKLtkEDIE 230
Cdd:cd16194  16 INASELQKILSIAL--ERAHTSKPREFGLRTCRQLIQCFDHGQNGKLALEEFQQLW---------------GYL--LEWQ 76

                        90       100
                ....*....|....*....|
gi 17136674 231 KVFSLYDRDNSGTIENEELK 250
Cdd:cd16194  77 AIFTKFDEDTSGTMDSYELR 96

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.

Pssm-ID: 238008 [Multi-domain] Cd Length: 63 Bit Score: 35.60 E-value: 3.02e-03

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 17136674  88 ELKSCFMEaYDDNQDGKIDIRELAQLLPMEEnflllfrfDNPLESsvEFMKIWREYDTDNSGYIEADELKNFLR 161
Cdd:cd00051   1 ELREAFRL-FDKDGDGTISADELKAALKSLG--------EGLSEE--EIDEMIREVDKDGDGKIDFEEFLELMA 63

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).

Pssm-ID: 320025 [Multi-domain] Cd Length: 263 Bit Score: 38.07 E-value: 4.43e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  30 RELKKLSANQFMDVWAHYDKDGNGYIEGTELdgFLREFvsSANATDISPEAVTDT-----MLEELKSCFMEAyDDNQDGK 104
Cdd:cd16227  64 RSFKMLDEEEANERFEEADEDGDGKVTWEEY--LADSF--GYDDEDNEEMIKDSTeddlkLLEDDKEMFEAA-DLNKDGK 138

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674 105 IDIRELAQLLPMEENflllfrfdnPLESSVEFMKIWREYDTDNSGYIEADElknFLRDLLKEAKKINDVSE-DKLIEYtd 183
Cdd:cd16227 139 LDKTEFSAFQHPEEY---------PHMHPVLIEQTLRDKDKDNDGFISFQE---FLGDRAGHEDKEWLLVEkDRFDED-- 204

                       170       180
                ....*....|....*....|...
gi 17136674 184 tmlqvFDANKDGRLQLSEMAKLL 206
Cdd:cd16227 205 -----YDKDGDGKLDGEEILSWL 222

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.

Pssm-ID: 425435 [Multi-domain] Cd Length: 29 Bit Score: 33.91 E-value: 5.45e-03

                          10        20
                  ....*....|....*....|....*....
gi 17136674   228 DIEKVFSLYDRDNSGTIENEELKGFLKDL 256
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKKL 29

EF-hand, calcium binding motif, found in secretagogin (SCGN); 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 calcium sensor/coincidence detector modulating vesicular exocytosis of neurotransmitters, neuropeptides or hormones. It also serves as a calcium buffer in neurons. Thus, SCGN may be linked to the pathogenesis of neurological diseases such as Alzheimer's, and also acts as a serum marker of neuronal damage, or as a tumor biomarker. SCGN consists of the three globular domains each of which contains a pair of EF-hand motifs. All six EF hand motifs of SCGN in some eukaryotes, including D. rerio, X. laevis, M. domestica, G. gallus, O. anatinus, could potentially bind six calcium ions. In contrast, SCGNs from higher eukaryotes have at least one non-functional EF-hand motif due to the mutation(s) or deletions. For instance, the EF1 loop does not coordinate calcium ion due to the key residue asparagine replaced by lysine in SCGNs of many mammalian species. Moreover, the EF2 loop seems to be competent for calcium-binding in most mammalian SCGNs except for human and chimpanzee orthologs.

Pssm-ID: 320078 [Multi-domain] Cd Length: 257 Bit Score: 37.77 E-value: 5.60e-03

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 17136674 236 YDRDNSGTIENEELKGFLKDLLELVKKDDYDAQDLAAF-EETIMRGVGTDKHGKISRKELTMILLtlakisPDDEE 310
Cdd:cd16178   8 FDADESGYIEGKELDNFFKDLLKKLGTKDTISADEVQDvKECFMSAYDVTGDGRIQIQELANIIL------PDDEN 77

EF-hand domain;

Pssm-ID: 463869 [Multi-domain] Cd Length: 30 Bit Score: 33.69 E-value: 6.03e-03

                          10        20
                  ....*....|....*....|....*....
gi 17136674   228 DIEKVFSLYDRDNSGTIENEELKGFLKDL 256
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKALRSL 29

EF-hand domain pair;

Pssm-ID: 463900 [Multi-domain] Cd Length: 67 Bit Score: 34.92 E-value: 6.25e-03

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 17136674    38 NQFMDVWAHYDKDGNGYIEGTELDGFLREFVSSANatdispeaVTDTMLEELKSCFmeayDDNQDGKIDIRELAQLL 114
Cdd:pfam13499   2 EKLKEAFKLLDSDGDGYLDVEELKKLLRKLEEGEP--------LSDEEVEELFKEF----DLDKDGRISFEEFLELY 66

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

Pssm-ID: 320059 [Multi-domain] Cd Length: 165 Bit Score: 36.86 E-value: 6.46e-03

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 17136674  48 DKDGNGYIEGTELDGFLrefvSSANATDISPEAvtdtmleelksCFM--EAYDDNQDGKIDIRELAQLlpmeenflllFR 125
Cdd:cd16184  10 DRDRSGKISAKELQQAL----VNGNWSHFNDET-----------CRLmiGMFDKDKSGTIDIYEFQAL----------WN 64

                        90       100       110
                ....*....|....*....|....*....|....*.
gi 17136674 126 FDNplessvEFMKIWREYDTDNSGYIEADELKNFLR 161
Cdd:cd16184  65 YIQ------QWKQVFQQFDRDRSGSIDENELHQALS 94

EF-hand, calcium binding motif, found in alpha-parvalbumin; Alpha-parvalbumin is cytosolic Ca2+/Mg2+-binding protein expressed mainly in fast-twitch skeletal myofibrils, where it may act as a soluble relaxing factor facilitating the Ca2+-mediated relaxation phase. It is also expressed in rapidly firing neurons, particularly GABA-ergic neurons, and thus may confer protection against Ca2+ toxicity. The major role of alpha-parvalbumin is metal buffering and transport of Ca2+. It binds different metal cations, and exhibits very high affinity for Ca2+ and physiologically significant affinity for Mg2+. Alpha-parvalbumin is characterized by the presence of three consecutive EF-hand motifs (helix-loop-helix) called AB, CD, and EF, but only CD and EF can chelate metal ions, such as Ca2+ and Mg2+. Both metal ion-binding sites in alpha-parvalbumin are high-affinity sites. Additionally, in contrast to beta-parvalbumin, alpha-parvalbumin is less acidic and has an additional residue in the C-terminal helix.

Pssm-ID: 319997 [Multi-domain] Cd Length: 101 Bit Score: 35.18 E-value: 9.30e-03

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 17136674 132 SSVEFMKIWREYDTDNSGYIEADELKNFLRDLLKEAKKINDvsedkliEYTDTMLQVFDANKDGRLQLSEMAKLL 206
Cdd:cd16254  32 SADDVKKVFHILDKDKSGFIEEDELKFVLKGFSPDGRDLSD-------KETKALLAAGDKDGDGKIGIDEFATLV 99