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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24641333  49 RQDTIDMEEIPLNQTNSQEPEDRRKMHEIFDKHDSDRDGLINTHELKELISDgycRDIPAYIADQILKRSDQDNDGHLDF 128
Cdd:COG5126  46 GDGRISREEFVAGMESLFEATVEPFARAAFDLLDTDGDGKISADEFRRLLTA---LGVSEEEADELFARLDTDGDGKISF 122

                ...
gi 24641333 129 EEF 131
Cdd:COG5126 123 EEF 125

Membrane-associated serine protease, rhomboid family [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24641333 178 PPLTMVLFsIIEIIMFLVDVIhfqddpnyqdrigesTSGPAATLFIYNPYKRYEG--WRFVSYMFVHVGIMHLMMNLIIQ 255
Cdd:COG0705   3 PPVTLALI-ALNVLVFLLQLL---------------LGGELLNWLALVPARLLLGelWRLLTSMFLHGGFLHLLFNMLAL 66

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24641333 256 IFLGIALELVHHWWRVGLVYLAGVLAGSMGTSLTSP--RIFLAGASGGVYALITAHIATIIMNYSEMEYAIVQLLAFLVF 333
Cdd:COG0705  67 WVFGPLLERRLGSKRFLLLYLLSGLGGGLLQLLFSPgsGYPLVGASGAIFGLLGALLVLGPRRRVLLLFIPIPALLFLLV 146

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*..
gi 24641333 334 CFtdlGTSVYRHLTDQhDQIGYVAHLSGAVAGLLVGIgVLRNLEVRR 380
Cdd:COG0705 147 WL---LLGLLFGLLGG-GGIAWEAHLGGLLAGLLLAL-LLRKLRRRR 188

rhomboid family GlyGly-CTERM serine protease; This model describes a rhomboid-like intramembrane serine protease. Its species distribution closely matches model TIGR03501, GlyGly-CTERM, which describes a protein targeting domain analogous to LPXTG and PEP-CTERM. In a number of species (Ralstonia eutropha ,R. metallidurans, R. solanacearum, Marinobacter aquaeolei, etc) with just one GlyGly-CTERM protein (i.e., a dedicated system), the rhombosortase and GlyGly-CTERM genes are adjacent.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24641333   219 ATLFIYNPY--KRYEGWRFVSYMFVHVGIMHLMMNLIIQIFLGIALELVHHWWRVGLVYLAGVLAGSMGTSLTSPRI-FL 295
Cdd:TIGR03902   1 SDLLAYDRAaiLDGEWWRLLTGHFVHLNWWHLLMNLAGLLLLWALFGRHLRARRLLLLLLLLSLLISLGLLLFLPSLqWY 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 24641333   296 AGASGGVYALITAHIATIIMNYSEMEYAIVQLLAF-LVFCFTDLGTSVYRHLTDQHdqIGYVAHLSGAVAGLLVGI 370
Cdd:TIGR03902  81 VGLSGVLHGLFAWGALRDIRYGRRSGWLLLLGVIAkLAWEQLFGASAFTAALIGAP--VATEAHLAGAISGLLIAL 154

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 24641333    71 RRKMHEIFDKHDSDRDGLINTHELKELISdGYCRDIPA--YIADQILKRSDQDNDGHLDFEEFYAM 134
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLR-KLEEGEPLsdEEVEELFKEFDLDKDGRISFEEFLEL 65

rhomboid-1 protease; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24641333  182 MVLFSIIEIIMFLVDVIHFQDDPnyqdrigestSGPAATLFI-----YNP-YKRYEGWRFVSYMFVHVGIMHLMMNLIIQ 255
Cdd:PTZ00101  56 IMAISIIQIIVFIISVSIKPADF----------LTPSDSLLVtlganVASrIKQGEIHRLILPIFLHANIFHTFFNVFFQ 125

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24641333  256 IFLGIALELVHHWWRVGLVYLAGVLAGSMGTSLTSPRIFLAGASGGVYALITAHIATIIMNYSEMEYAIVQLLAFLVFCF 335
Cdd:PTZ00101 126 LRMGFTLEKNYGIVKIIILYFLTGIYGNILSSSVTYCPIKVGASTSGMGLLGIVTSELILLWHVIRHRERVVFNIIFFSL 205

                        170       180       190       200       210       220
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 24641333  336 tdlgTSVYRHLTDQHDQIGYVAHLSGAVAGllVGIGVLRNLEVRRWERILWWVAVIVYFALMTTGII 402
Cdd:PTZ00101 206 ----ISFFYYFTFNGSNIDHVGHLGGLLSG--ISMGILYNSQMENKPSWYDHMKMASYACLALLAIV 266

CCC1-related family of proteins; CCC1_like: This protein family includes the proteins related to CCC1, a yeast vacuole transmembrane protein responsible for the iron and manganese transport from the cytosol into vacuole. It also includes the proteins similar to nodulin-21, a plant nodule-specific protein that may be involved in symbiotic nitrogen fixation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24641333 272 GLVYLAGVLAGSMGTSLTSPRIFLAGASGGVYA----LITAHIATiimnYSEMEY-AIVQLLAFLVFCFTDLGTSVYrhL 346
Cdd:cd01059  11 GLVSTFALVAGVAAAGDSTKAILLAGLAGLVAGaismAAGEYVSV----KSQRDKaALASGLSFILGGLLPLLPYLL--L 84

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|
gi 24641333 347 TDQHDQIGYVAHLSGAVAGLLVGIGVLRNLEVRRWERILwWVAVIVYFALMTTGIIIHVF 406
Cdd:cd01059  85 PAGSLALAVSVALVVALALFLLGAFVAKLGGAKKIRAAL-RMVVLGLLAAALTYLLGRLF 143

Membrane-associated serine protease, rhomboid family [Posttranslational modification, protein turnover, chaperones];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24641333 178 PPLTMVLFsIIEIIMFLVDVIhfqddpnyqdrigesTSGPAATLFIYNPYKRYEG--WRFVSYMFVHVGIMHLMMNLIIQ 255
Cdd:COG0705   3 PPVTLALI-ALNVLVFLLQLL---------------LGGELLNWLALVPARLLLGelWRLLTSMFLHGGFLHLLFNMLAL 66

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24641333 256 IFLGIALELVHHWWRVGLVYLAGVLAGSMGTSLTSP--RIFLAGASGGVYALITAHIATIIMNYSEMEYAIVQLLAFLVF 333
Cdd:COG0705  67 WVFGPLLERRLGSKRFLLLYLLSGLGGGLLQLLFSPgsGYPLVGASGAIFGLLGALLVLGPRRRVLLLFIPIPALLFLLV 146

                       170       180       190       200
                ....*....|....*....|....*....|....*....|....*..
gi 24641333 334 CFtdlGTSVYRHLTDQhDQIGYVAHLSGAVAGLLVGIgVLRNLEVRR 380
Cdd:COG0705 147 WL---LLGLLFGLLGG-GGIAWEAHLGGLLAGLLLAL-LLRKLRRRR 188

rhomboid family GlyGly-CTERM serine protease; This model describes a rhomboid-like intramembrane serine protease. Its species distribution closely matches model TIGR03501, GlyGly-CTERM, which describes a protein targeting domain analogous to LPXTG and PEP-CTERM. In a number of species (Ralstonia eutropha ,R. metallidurans, R. solanacearum, Marinobacter aquaeolei, etc) with just one GlyGly-CTERM protein (i.e., a dedicated system), the rhombosortase and GlyGly-CTERM genes are adjacent.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24641333   219 ATLFIYNPY--KRYEGWRFVSYMFVHVGIMHLMMNLIIQIFLGIALELVHHWWRVGLVYLAGVLAGSMGTSLTSPRI-FL 295
Cdd:TIGR03902   1 SDLLAYDRAaiLDGEWWRLLTGHFVHLNWWHLLMNLAGLLLLWALFGRHLRARRLLLLLLLLSLLISLGLLLFLPSLqWY 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 24641333   296 AGASGGVYALITAHIATIIMNYSEMEYAIVQLLAF-LVFCFTDLGTSVYRHLTDQHdqIGYVAHLSGAVAGLLVGI 370
Cdd:TIGR03902  81 VGLSGVLHGLFAWGALRDIRYGRRSGWLLLLGVIAkLAWEQLFGASAFTAALIGAP--VATEAHLAGAISGLLIAL 154

EF-hand domain pair;

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 24641333    71 RRKMHEIFDKHDSDRDGLINTHELKELISdGYCRDIPA--YIADQILKRSDQDNDGHLDFEEFYAM 134
Cdd:pfam13499   1 EEKLKEAFKLLDSDGDGYLDVEELKKLLR-KLEEGEPLsdEEVEELFKEFDLDKDGRISFEEFLEL 65

Eps15 homology domain; found in proteins implicated in endocytosis, vesicle transport, and signal transduction. The alignment contains a pair of EF-hand motifs, typically one of them is canonical and binds to Ca2+, while the other may not bind to Ca2+. A hydrophobic binding pocket is formed by residues from both EF-hand motifs. The EH domain binds to proteins containing NPF (class I), [WF]W or SWG (class II), or H[TS]F (class III) sequence motifs.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 24641333  76 EIFDKHDSDRDGLINTHELKE-LISDGycrdIPAYIADQILKRSDQDNDGHLDFEEFY-AMSL 136
Cdd:cd00052   3 QIFRSLDPDGDGLISGDEARPfLGKSG----LPRSVLAQIWDLADTDKDGKLDKEEFAiAMHL 61

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 24641333  73 KMHEIFDKHDSDRDGLINTHELKELIS-DGYCRDiPAYIAdQILKRSDQDNDGHLDFEEFYAM--SLRHKWMVRNMLTRY 149
Cdd:cd15898   1 WLRRQWIKADKDGDGKLSLKEIKKLLKrLNIRVS-EKELK-KLFKEVDTNGDGTLTFDEFEELykSLTERPELEPIFKKY 78

                ...
gi 24641333 150 CRY 152
Cdd:cd15898  79 AGT 81

XopAW family type III secretion system calcium-binding effector;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24641333   61 NQTNSQEPEDrrkmhEIFDKHDSDRDGLINTHELKELISDGyCRDIPAYIADQILKRSDQDNDGHLDFEEFYAMSlrhkw 140
Cdd:NF041410  21 SSARSQQFQK-----QLFAKLDSDGDGSVSQDELSSALSSK-SDDGSLIDLSELFSDLDSDGDGSLSSDELAAAA----- 89

                         90       100
                 ....*....|....*....|....*..
gi 24641333  141 mvrnmltrycryvvPPPKPLEGDEPDG 167
Cdd:NF041410  90 --------------PPPPPPPDQAPST 102

intramembrane serine protease GlpG; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24641333  224 YNPYKRYEGWRFVSYMFVHVGIMHLMMNLIIQIFLGIALELVHHWWRVGLVYLAGVLAGSMGTSLTSPrIFLAGASGGVY 303
Cdd:PRK10907 127 FDPSLKFELWRYFTHALLHFSLLHILFNLLWWWYLGGAVEKRLGSGKLIVITLISALLSGWVQSKFSG-PWFGGLSGVVY 205

                 ...
gi 24641333  304 ALI 306
Cdd:PRK10907 206 ALM 208

EF-hand, calcium binding motif, found in calumenin, reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins; The family corresponds to a group of six EF-hand Ca2+-binding proteins, including calumenin (also known as crocalbin or CBP-50), reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins. Calumenin is an endo/sarcoplasmic reticulum (ER/SR) resident low-affinity Ca2+-binding protein that contains six EF-hand domains and a C-terminal SR retention signal His-Asp-Glu-Phe (HDEF) tetrapeptide. It functions as a novel regulator of SERCA2, and its expressional changes are tightly coupled with Ca2+-cycling of cardiomyocytes. It is also broadly involved in haemostasis and in the pathophysiology of thrombosis. Moreover, the extracellular calumenin acts as a suppressor of cell migration and tumor metastasis. RCN-1 is an endoplasmic reticulum resident Ca2+-binding protein with a carboxyl-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide signal. It acts as a potential negative regulator of B-RAF activation and can negatively modulate cardiomyocyte hypertrophy by inhibition of the mitogen-activated protein kinase signalling cascade. It also plays a key role in the development of doxorubicin-associated resistance. RCN-3 is a putative six EF-hand Ca2+-binding protein that contains five RXXR (X is any amino acid) motifs and a C-terminal ER retrieval signal HDEL tetrapeptide. The RXXR motif represents the target sequence of subtilisin-like proprotein convertases (SPCs). RCN-3 is specifically bound to the paired basic amino-acid-cleaving enzyme-4 (PACE4) precursor protein and plays an important role in the biosynthesis of PACE4.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 24641333  68 PED-RRKMHEIFDKHDSDRDGLINTHELKELISdgYCRDipAYI---ADQILKRSDQDNDGHLDFEEF 131
Cdd:cd16226  30 PEEsKERLGIIVDKIDKNGDGFVTEEELKDWIK--YVQK--KYIredVDRQWKEYDPNKDGKLSWEEY 93

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 24641333  76 EIFDKHdSDRDG---LINTHELKELISD------GYCRDIPAYiaDQILKRSDQDNDGHLDFEEF 131
Cdd:cd00213  12 DVFHKY-SGKEGdkdTLSKKELKELLETelpnflKNQKDPEAV--DKIMKDLDVNKDGKVDFQEF 73

EF-hand motif found in phosphoinositide phospholipase C eta (PI-PLC-eta); PI-PLC-eta isozymes represent a class of neuron-specific metazoan PI-PLCs that are most abundant in the brain, particularly in the hippocampus, habenula, olfactory bulb, cerebellum, and throughout the cerebral cortex. They are phosphatidylinositol 4,5-bisphosphate-hydrolyzing enzymes that are more sensitive to Ca2+ than other PI-PLC isozymes. They function as calcium sensors activated by small increases in intracellular calcium concentrations. They are also activated through G-protein-coupled receptor (GPCR) stimulation, and further mediate GPCR signalling pathways. PI-PLC-eta isozymes contain an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core domain, a C2 domain, and a unique C-terminal tail that terminates with a PDZ-binding motif, a potential interaction site for other signaling proteins. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. The C-terminal tail harbors a number of proline-rich motifs which may interact with SH3 (Src homology 3) domain-containing proteins, as well as many serine/threonine residues, suggesting possible regulation of interactions by protein kinases/phosphatases. There are two PI-PLC-eta isozymes (1-2). Aside from the PI-PLC-eta isozymes identified in mammals, their eukaryotic homologs are also present in this family.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24641333  74 MHEIFDKHDSDRDGLINTHELKELISDgYCRDIPAYIADQILKRSDQD-NDGHLDFEEFYA----MSLRHKwmVRNMLTR 148
Cdd:cd16205   2 LKQTFEEADKNGDGLLSIGEILQLMHK-LNVNLPRRKVRQMFKEADTDdNQGTLDFEEFCAfykmMSTRRE--LYLLLLS 78

                .
gi 24641333 149 Y 149
Cdd:cd16205  79 Y 79

EF-hand, calcium binding motif, found in calumenin, reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins; The family corresponds to a group of six EF-hand Ca2+-binding proteins, including calumenin (also known as crocalbin or CBP-50), reticulocalbin-1 (RCN-1), reticulocalbin-3 (RCN-3), and similar proteins. Calumenin is an endo/sarcoplasmic reticulum (ER/SR) resident low-affinity Ca2+-binding protein that contains six EF-hand domains and a C-terminal SR retention signal His-Asp-Glu-Phe (HDEF) tetrapeptide. It functions as a novel regulator of SERCA2, and its expressional changes are tightly coupled with Ca2+-cycling of cardiomyocytes. It is also broadly involved in haemostasis and in the pathophysiology of thrombosis. Moreover, the extracellular calumenin acts as a suppressor of cell migration and tumor metastasis. RCN-1 is an endoplasmic reticulum resident Ca2+-binding protein with a carboxyl-terminal His-Asp-Glu-Leu (HDEL) tetrapeptide signal. It acts as a potential negative regulator of B-RAF activation and can negatively modulate cardiomyocyte hypertrophy by inhibition of the mitogen-activated protein kinase signalling cascade. It also plays a key role in the development of doxorubicin-associated resistance. RCN-3 is a putative six EF-hand Ca2+-binding protein that contains five RXXR (X is any amino acid) motifs and a C-terminal ER retrieval signal HDEL tetrapeptide. The RXXR motif represents the target sequence of subtilisin-like proprotein convertases (SPCs). RCN-3 is specifically bound to the paired basic amino-acid-cleaving enzyme-4 (PACE4) precursor protein and plays an important role in the biosynthesis of PACE4.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 24641333  68 PEDRRKMHEI-----FDKHDSDRDGLInthELKELISDGYcRDI-----PAYIAD---QILKRSDQDNDGHLDFEE 130
Cdd:cd16226 147 PEEFPHMRDIvvqetLEDIDKNKDGFI---SLEEYIGDMY-RDDdeeedPDWVKSereQFKEFRDKNKDGKMDREE 218

The penta-EF hand (PEF) family; The penta-EF hand (PEF) family contains a group of five EF-hand calcium-binding proteins, including several classical calpain large catalytic subunits (CAPN1, 2, 3, 8, 9, 11, 12, 13, 14), two calpain small subunits (CAPNS1 and CAPNS2), as well as non-calpain PEF proteins, ALG-2 (apoptosis-linked gene 2, also termed programmed cell death protein 6, PDCD6), peflin, sorcin, and grancalcin. Based on the sequence similarity of EF1 hand, ALG-2 and peflin have been classified into group I PEF proteins. Calcium-dependent protease calpain subfamily members, sorcin and grancalcin, are group II PEF proteins. Calpains (EC 3.4.22.17) are calcium-activated intracellular cysteine proteases that play important roles in the degradation or functional modulation in a variety of substrates. They have been implicated in a number of physiological processes such as cell cycle progression, remodeling of cytoskeletal-cell membrane attachments, signal transduction, gene expression and apoptosis. ALG-2 is a pro-apoptotic factor that forms a homodimer in the cell or a heterodimer with its closest paralog peflin through their EF5s. Peflin is a 30-kD PEF protein with a longer N-terminal hydrophobic domain than any other member of the PEF family, and it contains nine nonapeptide (A/PPGGPYGGP) repeats. It exists only as a heterodimer with ALG-2. The dissociation of heterodimer occurs in the presence of Ca2+. ALG-2 interacts with various proteins in a Ca2+-dependent manner. Sorcin (for soluble resistance-related calcium binding protein) is a soluble resistance-related calcium-binding protein that participates in the regulation of calcium homeostasis in cells. Grancalcin is a cytosolic Ca2+-binding protein specifically expressed in neutrophils and monocytes/macrophages. It plays a key role in leukocyte-specific functions that are responsible for host defense. Grancalcin can form a heterodimer together with sorcin. Members in this family contain five EF-hand motifs attached to an N-terminal region of variable length containing one or more short Gly/Pro-rich sequences. These proteins form homodimers or heterodimers through pairing between the 5th EF-hands from the two molecules. Unlike calmodulin, the PEF domains do not undergo major conformational changes upon binding Ca2+.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 24641333  74 MHEIFDKHDSDRDGLINTHELKELISD-GYcrDIPAYIADQILKRSDQDNdGHLDFEEFYAMSLRHKWMVR 143
Cdd:cd15897  72 WQEIFRTYDTDGSGTIDSNELRQALSGaGY--RLSEQTYDIIIRRYDRGR-GNIDFDDFIQCCVRLQRLTD 139

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

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 24641333  71 RRKMHEIFDKHDSDRDGLINTHELKELISDGYCRDIPAyIADQILKRSDQDNDGHLDFEEF 131
Cdd:COG5126  32 RRLWATLFSEADTDGDGRISREEFVAGMESLFEATVEP-FARAAFDLLDTDGDGKISADEF 91

calmodulin; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 24641333   52 TIDMEE-IPLNQTNSQEPEDRRKMHEIFDKHDSDRDGLINTHELKE-LISDGycRDIPAYIADQILKRSDQDNDGHLDFE 129
Cdd:PTZ00184  63 TIDFPEfLTLMARKMKDTDSEEEIKEAFKVFDRDGNGFISAAELRHvMTNLG--EKLTDEEVDEMIREADVDGDGQINYE 140

                 ....*
gi 24641333  130 EFYAM 134
Cdd:PTZ00184 141 EFVKM 145

EF-hand domain;

                          10        20
                  ....*....|....*....|....*.
gi 24641333    73 KMHEIFDKHDSDRDGLINTHELKELI 98
Cdd:pfam13405   1 ELREAFKLFDKDGDGKISLEELRKAL 26

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).

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gi 24641333  78 FDKHDSDRDGLINTHELKELISDGycrdIPAY---IADQILKRSDQDNDGHLDFEEFYAMslrHKW 140
Cdd:cd16185   6 FRAVDRDRSGSIDVNELQKALAGG----GLLFslaTAEKLIRMFDRDGNGTIDFEEFAAL---HQF 64

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

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gi 24641333  65 SQEPEDRRKMHEIFDKhdsDRDGLINTHELKELI----SDGycRDIPAYIADQILKRSDQDNDGHLDFEEFYAM 134
Cdd:cd16251  30 QKSEDQIKKVFQILDK---DKSGFIEEEELKYILkgfsIAG--RDLTDEETKALLAAGDTDGDGKIGVEEFATL 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.

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gi 24641333    73 KMHEIFDKHDSDRDGLINTHELKELISD 100
Cdd:pfam00036   1 ELKEIFRLFDKDGDGKIDFEEFKELLKK 28

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.

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gi 24641333     73 KMHEIFDKHDSDRDGLINTHELKELIS 99
Cdd:smart00054   1 ELKEAFRLFDKDGDGKIDFEEFKDLLK 27

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.

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gi 24641333  76 EIFDKHDSDRDGLINTHELKELISD--------GYCRDIPAYIADQILKRSDQDNDGHLDFEEF 131
Cdd:cd15902   3 EVWMHFDADGNGYIEGKELDSFLREllkalngkDKTDDEVAEKKKEFMEKYDENEDGKIEIREL 66

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).

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gi 24641333  69 EDRRKMHEIFDKHDSDRDGLINTHELKELISDGYcRDIPAYIADQILKRSDQDNDGHLDFEEF 131
Cdd:cd16227  33 EAKRRLAVLAKKMDLNDDGFIDRKELKAWILRSF-KMLDEEEANERFEEADEDGDGKVTWEEY 94