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0GNRP_HUMAN*   SwissProt (?) | Description Local Annotation Link Reference
General Information
DescriptionGuanine nucleotide-releasing protein (gnrp) (ras-specific nucleotide exchange factor cdc25) (ras-specific guanine nucleotide-releasing factor).
SpeciesHomo sapiens (NCBI taxonomy ID: 9606)
GO0005886 plasma membrane (NAS)
0019717 synaptosome (NAS)
0005088 Ras guanyl-nucleotide exchange factor activity (TAS)
0007616 long-term memory (NAS)
0007165 signal transduction (TAS)

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Domain Architecture (Details)
InterPro domains unassigned to SynO:
This domain is found in several guanine nucleotide exchange factors for Ras-like small GTPases.nd liesN-terminal to the RasGef (Cdc25-like) domain. Proteins belonging to this family include guanine nucleotidedissociation stimulator.hich stimulates the dissociation of GDP from the Ras-related RalA and RalBGTPases and allows GTP binding and activation of the GTPases; GTPase-activating protein (GAP) for Rho1and Rho2.hich is involved in the control of cellular morphogenesis; and the yeast cell division controlprotein.hich promotes the exchange of Ras-bound GDP by GTP and controls the level of cAMP whenthe cell division cycle is triggered. Also included is the son of sevenless protein.hich promotes theexchange of Ras-bound GDP by GTP during neuronal development.
  IPR000651:Guanine nucleotide exchange factor for Ras-like GTPases, N-terminal
The pleckstrin homology (PH) domain is a domain of about 100 residues that occurs in a wide range of proteins involved in intracellular signaling or as constituents of the cytoskeleton .The function of this domain is not clear.everal putative functions have been suggested:binding to the beta/gamma subunit of heterotrimeric G proteins.inding to lipids..g. phosphatidylinositol-4.-bisphosphate.inding to phosphorylated Ser/Thr residues.ttachment to membranes by an unknown mechanism.It is possible that different PH domains have totally different ligand requirements.The 3D structure of several PH domains has been determined . All known cases have a common structure consisting of two perpendicular anti-parallel beta sheets.ollowed by a C-terminal amphipathic helix. The loops connecting the beta-strands differ greatly in length.aking the PH domain relatively difficult to detect. There are no totally invariant residues within the PH domain.Proteins reported to contain one more PH domains belong to the following families:Pleckstrin.he protein where this domain was first detected.s the major substrate of protein kinase C in platelets. Pleckstrin is one of the rare proteins to contains two PH domains.Ser/Thr protein kinases such as the Akt/Rac family.he beta-adrenergic receptor kinases.he mu isoform of PKC and the trypanosomal NrkA family.Tyrosine protein kinases belonging to the Btk/Itk/Tec subfamily.Insulin Receptor Substrate 1 (IRS-1).Regulators of small G-proteins like guanine nucleotide releasing factor GNRP (Ras-GRF) (which contains 2 PH domains).uanine nucleotide exchange proteins like and Saccharomyces cerevisiae CDC24.TPase activating proteins like rasGAP and BEM2/IPL2.nd the human break point cluster protein bcr.Cytoskeletal proteins such as dynamin (see ).aenorhabditis elegans kinesin-like protein unc-104 (see ).pectrin beta-chain.yntrophin (2 PH domains) and S. cerevisiae nuclear migration protein NUM1.Mammalian phosphatidylinositol-specific phospholipase C (PI-PLC) (see ) isoforms gamma and delta. Isoform gamma contains two PH domains.he second one is split into two parts separated by about 400 residues.Oxysterol binding proteins OSBP.. cerevisiae OSH1 and YHR073w.Mouse protein citron. putative rho/rac effector that binds to the GTP-bound forms of rho and rac.Several S. cerevisiae proteins involved in cell cycle regulation and bud formation like BEM2.EM3.UD4 and the BEM1-binding proteins BOI2 (BEB1) and BOI1 (BOB1).C. elegans protein MIG-10.C. elegans hypothetical proteins C04D8.1.06H7.4 and ZK632.12.S. cerevisiae hypothetical proteins YBR129c and YHR155w.
Calmodulin (CaM) is recognized as a major calcium sensor and orchestrator of regulatory events through its interaction with a diverse group of cellular proteins. Three classes of recognition motifs exist for many of the known CaM binding proteins; the IQ motif as a consensus for Ca2+-independent binding and two related motifs for Ca2+-dependent binding.ermed18-14 and 1-5-10 based on the position of conserved hydrophobic residues .The regulatory domain of scallop myosin is a three-chain protein complex that switches on this motor in response to Ca2+ binding. Side-chain interactions link the two light chains in tandem to adjacent segments of the heavy chain bearing the IQ-sequence motif. The Ca2+-binding site is a novel EF-hand motif on the essential light chain and is stabilized by linkages involving the heavy chain and both light chains.ccounting for the requirement of all three chains for Ca2+ binding and regulation in the intact myosin molecule .
  IPR000048:IQ calmodulin-binding region
The Rho family GTPases and CDC42 regulate a diverse array of cellularprocesses. Like all members of the Ras superfamily.he Rho proteins cycle between active GTP-bound and inactive GDP-bound conformational states.Activation of Rho proteins through release of bound GDP and subsequentbinding of GTP.s catalyzed by guanine nucleotide exchange factors (GEFs) inthe Dbl family. The proteins encoded by members of the Dbl family share acommon domain.resented in this entry.f about 200 residues (designated the Dbl homology or DH domain)that has been shown to encode a GEF activity specific for a number of Rhofamily members. In addition.ll family members possess a second.hareddomain designated the pleckstrin homology (PH) domain (). Trioand its homolog UNC-73 are unique within the Dbl family insomuch as theyencode two distinct DH/PH domain modules. The PH domain is invariably locatedimmediately C-terminal to the DH domain and this invariant topography suggestsa functional interdependence between these two structural modules. Biochemicaldata have established the role of the conserved DH domain in Rho GTPaseinteraction and activation.nd the role of the tandem PH domain inintracellular targeting and/or regulation of DH domain function. The DH domainof Dbl has been shown to mediate oligomerization that is mostly homophilic innature. In addition to the tandem DH/PH domains Dbl family GEFs containdiverse structural motifs like serine/threonine kinase.BD.DZ.GS.Q.EM.dc25RasGEF.H.H2.H3.F.pectrin or Ig.The DH domain is composed of three structurally conserved regions separated bymore variable regions. It does not share significant sequence homology withother subtypes of small G-protein GEF motifs such as the Cdc25 domain and theSec7 domain.hich specifically interact with Ras and ARFfamily small GTPases.espectively.or with other Rho protein interactivemotifs.ndicating that the Dbl family proteins are evolutionarily unique. TheDH domain is composed of 11 alpha helices that are folded into a flattened.longated alpha-helix bundle in which two of the three conserved regions.onserved region 1 (CR1) and conserved region 3 (CR3).re exposed near thecenter of one surface. CR1 and CR3.ogether with a part of alpha-6 and theDH/PH junction site.onstitute the Rho GTPase interacting pocket.
Ras proteins are membrane-associated molecular switches that bind GTP and GDP and slowly hydrolyze GTP to GDP . The balance between the GTP bound (active) and GDP bound (inactive) states is regulated by the opposite action of proteins activating the GTPase activity and that of proteins which promote the loss of bound GDP and the uptake of fresh GTP . The latter proteins are known as guanine-nucleotide dissociation stimulators (GDSs) (or also as guanine-nucleotide releasing (or exchange) factors (GRFs)). Proteins that act as GDS can be classified into at least two families.n the basis of sequence similarities.he CDC24 family (see ) and the CDC25 family.The size of the proteins of the CDC25 family range from 309 residues (LTE1) to 1596 residues (sos). The sequence similarity shared by all these proteins is limited to a region of about 250 amino acids generally located in their C-terminal section (currently the only exceptions are sos and ralGDS where this domain makes up the central part of the protein). This domain has been shown.n CDC25 an SCD25.o be essential for the activity of these proteins.
  IPR001895:Guanine-nucleotide dissociation stimulator CDC25
Small GTPases of the Ras family alternate between 2 conformations induced by the binding of either GTP or GDP. Guanine nucleotide exchange factors (GEFs) induce the dissociation of GDP to allow association of the more abundant GTP. The Ras-like family of small GTPases includes.mong Ral. The family is characterized by similarities in the effector domain. The Ras GTPase Rap1 is activated rapidly in response to activation of a variety of receptors. Rap1 activation is mediated by several second messengers.ncluding calcium.iacylglycerol.nd cAMP. GEFs have been identified that mediate these effects. One such GEF is Epac.n exchange protein directly activated by cAMP.hich represents a novel cAMP-induced.rotein kinase A-independent pathway .The SSF signature in this entry is currently under review. Please be aware that some of the protein hits may be false positives.
  IPR008937:Ras guanine nucleotide exchange factor
Pleckstrin homology (PH) domains are small modular domains that occur once.r occasionally several times.n a large variety of signalling they serve as simple targeting domains that recognize only phosphoinositide headgroups . PH domains can target their host protein to the plasma and internal membranes through its association with phosphoinositides. PH domains have a partly opened beta-barrel topology that is capped by an alpha helix. Proteins containing PH domains include pleckstrin (N-terminal).hospholipase C and Rac-alpha kinase.The structure of PH domains is similar to the phosphotyrosine-binding domain (PTB) found in IRS-1 (insulin receptor substrate 1).hc adaptor and Numb; to the Ran-binding domain.ound in Nup nuclear pore complex and Ranbp1; to the Enabled/VASP homology domain 1 (EVH1 domain).ound in Enabled.ASP (vasodilator-stimulated phosphoprotein).omer and WASP actin regulatory protein; to the third domain of FERM.ound in moesin.adixin.zrin.erlin and talin; and to the PH-like domain of neurobeachin.
  IPR011993:Pleckstrin homology-type
SequencesProtein: GNRP_HUMAN (1275 aa)
mRNA: NM_002891
Local Annotation
Synapse Ontology
introduce the substructure of the synapse and the location where the molecule can be seen. It will contain all the constructive special organelle and molecule we known.
sdb:0001 Structure/Biochemistry of synapse  (Evidence:keywords)
KO assignmentK04349
  Level 3 annotation:
    Ras guanine nucleotide-releasing factor
  Level 2 annotation:
    MAPK signaling pathway
Loci Structure (Details)Loci index, Chromosomal location, Length, Possible relational loci clusterExon1: 98 residues, 77041340-77041633Exon2: 25 residues, 77051262-77051331Exon3: 41 residues, 77052699-77052817Exon4: 28 residues, 77060016-77060096Exon5: 68 residues, 77064403-77064601Exon6: 30 residues, 77069585-77069670Exon7: 36 residues, 77071087-77071191Exon8: 22 residues, 77075136-77075197Exon9: 39 residues, 77077492-77077605Exon10: 37 residues, 77078115-77078222Exon11: 59 residues, 77079139-77079310Exon12: 44 residues, 77081058-77081184Exon13: 126 residues, 77083198-77083572Exon14: 88 residues, 77085573-77085831Exon15: 15 residues, 77091885-77091924Exon16: 29 residues, 77094723-77094806Exon17: 47 residues, 77097166-77097303Exon18: 23 residues, 77099437-77099501Exon19: 55 residues, 77104710-77104871Exon20: 41 residues, 77107137-77107256Exon21: 38 residues, 77110796-77110906Exon22: 66 residues, 77111519-77111713Exon23: 28 residues, 77114527-77114607Exon24: 86 residues, 77126142-77126396Exon25: 33 residues, 77128892-77128985Exon26: 51 residues, 77137730-77137878Exon27: 37 residues, 77143816-77143923Exon28: 94 residues, 77169619-77169895Exon29: 2 residues, -Jump to GNRP_HUMAN  
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Loci Cluster (Details)Loci: 2903 76644960-76673513 ~-29K 12833(CHRNA5)(+)Loci: 4183 76672451-76700692 ~-28K 12834(-)Loci: 4184 76703690-76720642 ~-17K 12836(CHRNB4)(-)Loci: 4185 77041340-77169895 ~-129K 12842(RASGRF1)(-)Loci: 2902 76228773-76249938 ~-21K 12813(IDH3A)(+)Link out to UCSC