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| | ==Crystal Structure of the RA and PH Domains of Grb10== | | ==Crystal Structure of the RA and PH Domains of Grb10== |
| - | <StructureSection load='3hk0' size='340' side='right' caption='[[3hk0]], [[Resolution|resolution]] 2.60Å' scene=''> | + | <StructureSection load='3hk0' size='340' side='right'caption='[[3hk0]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3hk0]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HK0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3HK0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3hk0]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HK0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3HK0 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SCN:THIOCYANATE+ION'>SCN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GRB10, GRBIR, KIAA0207 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GRB10, GRBIR, KIAA0207 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3hk0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hk0 OCA], [http://pdbe.org/3hk0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3hk0 RCSB], [http://www.ebi.ac.uk/pdbsum/3hk0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3hk0 ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3hk0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hk0 OCA], [https://pdbe.org/3hk0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3hk0 RCSB], [https://www.ebi.ac.uk/pdbsum/3hk0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3hk0 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GRB10_HUMAN GRB10_HUMAN]] Adapter protein which modulates coupling of a number of cell surface receptor kinases with specific signaling pathways. Binds to, and suppress signals from, activated receptors tyrosine kinases, including the insulin (INSR) and insulin-like growth factor (IGF1R) receptors. The inhibitory effect can be achieved by 2 mechanisms: interference with the signaling pathway and increased receptor degradation. Delays and reduces AKT1 phosphorylation in response to insulin stimulation. Blocks association between INSR and IRS1 and IRS2 and prevents insulin-stimulated IRS1 and IRS2 tyrosine phosphorylation. Recruits NEDD4 to IGF1R, leading to IGF1R ubiquitination, increased internalization and degradation by both the proteasomal and lysosomal pathways. May play a role in mediating insulin-stimulated ubiquitination of INSR, leading to proteasomal degradation. Negatively regulates Wnt signaling by interacting with LRP6 intracellular portion and interfering with the binding of AXIN1 to LRP6. Positive regulator of the KDR/VEGFR-2 signaling pathway. May inhibit NEDD4-mediated degradation of KDR/VEGFR-2.<ref>PMID:12493740</ref> <ref>PMID:15060076</ref> <ref>PMID:16434550</ref> <ref>PMID:17376403</ref> | + | [[https://www.uniprot.org/uniprot/GRB10_HUMAN GRB10_HUMAN]] Adapter protein which modulates coupling of a number of cell surface receptor kinases with specific signaling pathways. Binds to, and suppress signals from, activated receptors tyrosine kinases, including the insulin (INSR) and insulin-like growth factor (IGF1R) receptors. The inhibitory effect can be achieved by 2 mechanisms: interference with the signaling pathway and increased receptor degradation. Delays and reduces AKT1 phosphorylation in response to insulin stimulation. Blocks association between INSR and IRS1 and IRS2 and prevents insulin-stimulated IRS1 and IRS2 tyrosine phosphorylation. Recruits NEDD4 to IGF1R, leading to IGF1R ubiquitination, increased internalization and degradation by both the proteasomal and lysosomal pathways. May play a role in mediating insulin-stimulated ubiquitination of INSR, leading to proteasomal degradation. Negatively regulates Wnt signaling by interacting with LRP6 intracellular portion and interfering with the binding of AXIN1 to LRP6. Positive regulator of the KDR/VEGFR-2 signaling pathway. May inhibit NEDD4-mediated degradation of KDR/VEGFR-2.<ref>PMID:12493740</ref> <ref>PMID:15060076</ref> <ref>PMID:16434550</ref> <ref>PMID:17376403</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | ==See Also== | | ==See Also== |
| - | *[[Growth factor receptor-bound protein|Growth factor receptor-bound protein]] | + | *[[Growth factor receptor-bound proteins 3D structures|Growth factor receptor-bound proteins 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Human]] | | [[Category: Human]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Depetris, R S]] | | [[Category: Depetris, R S]] |
| | [[Category: Hubbard, S R]] | | [[Category: Hubbard, S R]] |
| Structural highlights
Function
[GRB10_HUMAN] Adapter protein which modulates coupling of a number of cell surface receptor kinases with specific signaling pathways. Binds to, and suppress signals from, activated receptors tyrosine kinases, including the insulin (INSR) and insulin-like growth factor (IGF1R) receptors. The inhibitory effect can be achieved by 2 mechanisms: interference with the signaling pathway and increased receptor degradation. Delays and reduces AKT1 phosphorylation in response to insulin stimulation. Blocks association between INSR and IRS1 and IRS2 and prevents insulin-stimulated IRS1 and IRS2 tyrosine phosphorylation. Recruits NEDD4 to IGF1R, leading to IGF1R ubiquitination, increased internalization and degradation by both the proteasomal and lysosomal pathways. May play a role in mediating insulin-stimulated ubiquitination of INSR, leading to proteasomal degradation. Negatively regulates Wnt signaling by interacting with LRP6 intracellular portion and interfering with the binding of AXIN1 to LRP6. Positive regulator of the KDR/VEGFR-2 signaling pathway. May inhibit NEDD4-mediated degradation of KDR/VEGFR-2.[1] [2] [3] [4]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Growth factor receptor-binding proteins Grb7, Grb10 and Grb14 are adaptor proteins containing a Ras-associating (RA) domain, a pleckstrin-homology (PH) domain, a family-specific BPS (between PH and SH2) region and a C-terminal Src-homology-2 domain. Previous structural studies showed that the Grb14 BPS region binds as a pseudosubstrate inhibitor in the tyrosine kinase domain of the insulin receptor to suppress insulin signaling. Here we report the crystal structure of the RA and PH domains of Grb10 at 2.6-A resolution. The structure reveals that these two domains, along with the intervening linker, form an integrated, dimeric structural unit. Biochemical studies demonstrated that Grb14 binds to activated Ras, which may serve as a timing mechanism for downregulation of insulin signaling. Our results illuminate the membrane-recruitment mechanisms not only of Grb7, Grb10 and Grb14 but also of MIG-10, Rap1-interacting adaptor molecule, lamellipodin and Pico, proteins involved in actin-cytoskeleton rearrangement that share a structurally related RA-PH tandem unit.
Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14.,Depetris RS, Wu J, Hubbard SR Nat Struct Mol Biol. 2009 Aug;16(8):833-9. Epub 2009 Aug 2. PMID:19648926[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wick KR, Werner ED, Langlais P, Ramos FJ, Dong LQ, Shoelson SE, Liu F. Grb10 inhibits insulin-stimulated insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association of IRS-1/IRS-2 with the insulin receptor. J Biol Chem. 2003 Mar 7;278(10):8460-7. Epub 2002 Dec 18. PMID:12493740 doi:http://dx.doi.org/10.1074/jbc.M208518200
- ↑ Murdaca J, Treins C, Monthouel-Kartmann MN, Pontier-Bres R, Kumar S, Van Obberghen E, Giorgetti-Peraldi S. Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation. J Biol Chem. 2004 Jun 18;279(25):26754-61. Epub 2004 Apr 1. PMID:15060076 doi:http://dx.doi.org/10.1074/jbc.M311802200
- ↑ Ramos FJ, Langlais PR, Hu D, Dong LQ, Liu F. Grb10 mediates insulin-stimulated degradation of the insulin receptor: a mechanism of negative regulation. Am J Physiol Endocrinol Metab. 2006 Jun;290(6):E1262-6. Epub 2006 Jan 24. PMID:16434550 doi:http://dx.doi.org/10.1152/ajpendo.00609.2005
- ↑ Tezuka N, Brown AM, Yanagawa S. GRB10 binds to LRP6, the Wnt co-receptor and inhibits canonical Wnt signaling pathway. Biochem Biophys Res Commun. 2007 May 11;356(3):648-54. Epub 2007 Mar 12. PMID:17376403 doi:http://dx.doi.org/10.1016/j.bbrc.2007.03.019
- ↑ Depetris RS, Wu J, Hubbard SR. Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14. Nat Struct Mol Biol. 2009 Aug;16(8):833-9. Epub 2009 Aug 2. PMID:19648926 doi:10.1038/nsmb.1642
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