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| - | [[Image:1gcq.jpg|left|200px]]<br /><applet load="1gcq" size="350" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1gcq, resolution 1.68Å" /> | |
| - | '''CRYSTAL STRUCTURE OF VAV AND GRB2 SH3 DOMAINS'''<br /> | |
| | | | |
| - | ==Overview== | + | ==CRYSTAL STRUCTURE OF VAV AND GRB2 SH3 DOMAINS== |
| - | Vav is a guanine nucleotide exchange factor for the Rho/Rac family that is, expressed exclusively in hematopoietic cells. Growth factor receptor-bound, protein 2 (Grb2) has been proposed to play important roles in the membrane, localization and activation of Vav through dimerization of its C-terminal, Src-homology 3 (SH3) domain (GrbS) and the N-terminal SH3 domain of Vav, (VavS). The crystal structure of VavS complexed with GrbS has been solved., VavS is distinct from other SH3 domain proteins in that its binding site, for proline-rich peptides is blocked by its own RT loop. One of the ends, of the VavS beta-barrel forms a concave hydrophobic surface. The GrbS, components make a contiguous complementary interface with the VavS, surface. The binding site of GrbS for VavS partially overlaps with the, canonical binding site for proline-rich peptides, but is definitely, different. Mutations at the interface caused a decrease in the binding, affinity of VavS for GrbS by 4- to 40-fold. The structure reveals how GrbS, discriminates VavS specifically from other signaling molecules without, binding to the proline-rich motif. | + | <StructureSection load='1gcq' size='340' side='right'caption='[[1gcq]], [[Resolution|resolution]] 1.68Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1gcq]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GCQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1GCQ FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.68Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MRD:(4R)-2-METHYLPENTANE-2,4-DIOL'>MRD</scene></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=1gcq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1gcq OCA], [https://pdbe.org/1gcq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1gcq RCSB], [https://www.ebi.ac.uk/pdbsum/1gcq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1gcq ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/GRB2_HUMAN GRB2_HUMAN] Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.<ref>PMID:1322798</ref> <ref>PMID:8178156</ref> <ref>PMID:19815557</ref> Isoform 2 does not bind to phosphorylated epidermal growth factor receptor (EGFR) but inhibits EGF-induced transactivation of a RAS-responsive element. Isoform 2 acts as a dominant negative protein over GRB2 and by suppressing proliferative signals, may trigger active programmed cell death.<ref>PMID:1322798</ref> <ref>PMID:8178156</ref> <ref>PMID:19815557</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/gc/1gcq_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1gcq ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Vav is a guanine nucleotide exchange factor for the Rho/Rac family that is expressed exclusively in hematopoietic cells. Growth factor receptor-bound protein 2 (Grb2) has been proposed to play important roles in the membrane localization and activation of Vav through dimerization of its C-terminal Src-homology 3 (SH3) domain (GrbS) and the N-terminal SH3 domain of Vav (VavS). The crystal structure of VavS complexed with GrbS has been solved. VavS is distinct from other SH3 domain proteins in that its binding site for proline-rich peptides is blocked by its own RT loop. One of the ends of the VavS beta-barrel forms a concave hydrophobic surface. The GrbS components make a contiguous complementary interface with the VavS surface. The binding site of GrbS for VavS partially overlaps with the canonical binding site for proline-rich peptides, but is definitely different. Mutations at the interface caused a decrease in the binding affinity of VavS for GrbS by 4- to 40-fold. The structure reveals how GrbS discriminates VavS specifically from other signaling molecules without binding to the proline-rich motif. |
| | | | |
| - | ==Disease==
| + | Novel recognition mode between Vav and Grb2 SH3 domains.,Nishida M, Nagata K, Hachimori Y, Horiuchi M, Ogura K, Mandiyan V, Schlessinger J, Inagaki F EMBO J. 2001 Jun 15;20(12):2995-3007. PMID:11406576<ref>PMID:11406576</ref> |
| - | Known diseases associated with this structure: Central hypoventilation syndrome, congenital OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=100790 100790]], Haddad syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=100790 100790]]
| + | |
| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | 1GCQ is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=MRD:'>MRD</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GCQ OCA].
| + | </div> |
| | + | <div class="pdbe-citations 1gcq" style="background-color:#fffaf0;"></div> |
| | | | |
| - | ==Reference== | + | ==See Also== |
| - | Novel recognition mode between Vav and Grb2 SH3 domains., Nishida M, Nagata K, Hachimori Y, Horiuchi M, Ogura K, Mandiyan V, Schlessinger J, Inagaki F, EMBO J. 2001 Jun 15;20(12):2995-3007. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11406576 11406576]
| + | *[[Growth factor receptor-bound proteins 3D structures|Growth factor receptor-bound proteins 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Mus musculus]] | | [[Category: Mus musculus]] |
| - | [[Category: Protein complex]]
| + | [[Category: Hachimori Y]] |
| - | [[Category: Hachimori, Y.]] | + | [[Category: Inagaki F]] |
| - | [[Category: Inagaki, F.]] | + | [[Category: Nagata K]] |
| - | [[Category: Nagata, K.]] | + | [[Category: Nishida M]] |
| - | [[Category: Nishida, M.]] | + | [[Category: Ogura K]] |
| - | [[Category: Ogura, K.]] | + | |
| - | [[Category: MRD]]
| + | |
| - | [[Category: grb2]]
| + | |
| - | [[Category: protein-protein complex]]
| + | |
| - | [[Category: sh3 domain]]
| + | |
| - | [[Category: vav]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 15:52:34 2008''
| + | |
| Structural highlights
Function
GRB2_HUMAN Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.[1] [2] [3] Isoform 2 does not bind to phosphorylated epidermal growth factor receptor (EGFR) but inhibits EGF-induced transactivation of a RAS-responsive element. Isoform 2 acts as a dominant negative protein over GRB2 and by suppressing proliferative signals, may trigger active programmed cell death.[4] [5] [6]
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
Vav is a guanine nucleotide exchange factor for the Rho/Rac family that is expressed exclusively in hematopoietic cells. Growth factor receptor-bound protein 2 (Grb2) has been proposed to play important roles in the membrane localization and activation of Vav through dimerization of its C-terminal Src-homology 3 (SH3) domain (GrbS) and the N-terminal SH3 domain of Vav (VavS). The crystal structure of VavS complexed with GrbS has been solved. VavS is distinct from other SH3 domain proteins in that its binding site for proline-rich peptides is blocked by its own RT loop. One of the ends of the VavS beta-barrel forms a concave hydrophobic surface. The GrbS components make a contiguous complementary interface with the VavS surface. The binding site of GrbS for VavS partially overlaps with the canonical binding site for proline-rich peptides, but is definitely different. Mutations at the interface caused a decrease in the binding affinity of VavS for GrbS by 4- to 40-fold. The structure reveals how GrbS discriminates VavS specifically from other signaling molecules without binding to the proline-rich motif.
Novel recognition mode between Vav and Grb2 SH3 domains.,Nishida M, Nagata K, Hachimori Y, Horiuchi M, Ogura K, Mandiyan V, Schlessinger J, Inagaki F EMBO J. 2001 Jun 15;20(12):2995-3007. PMID:11406576[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 1992 Aug 7;70(3):431-42. PMID:1322798
- ↑ Fath I, Schweighoffer F, Rey I, Multon MC, Boiziau J, Duchesne M, Tocque B. Cloning of a Grb2 isoform with apoptotic properties. Science. 1994 May 13;264(5161):971-4. PMID:8178156
- ↑ Pao-Chun L, Chan PM, Chan W, Manser E. Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling. J Biol Chem. 2009 Dec 11;284(50):34954-63. doi: 10.1074/jbc.M109.072660. Epub, 2009 Oct 8. PMID:19815557 doi:10.1074/jbc.M109.072660
- ↑ Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell. 1992 Aug 7;70(3):431-42. PMID:1322798
- ↑ Fath I, Schweighoffer F, Rey I, Multon MC, Boiziau J, Duchesne M, Tocque B. Cloning of a Grb2 isoform with apoptotic properties. Science. 1994 May 13;264(5161):971-4. PMID:8178156
- ↑ Pao-Chun L, Chan PM, Chan W, Manser E. Cytoplasmic ACK1 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling. J Biol Chem. 2009 Dec 11;284(50):34954-63. doi: 10.1074/jbc.M109.072660. Epub, 2009 Oct 8. PMID:19815557 doi:10.1074/jbc.M109.072660
- ↑ Nishida M, Nagata K, Hachimori Y, Horiuchi M, Ogura K, Mandiyan V, Schlessinger J, Inagaki F. Novel recognition mode between Vav and Grb2 SH3 domains. EMBO J. 2001 Jun 15;20(12):2995-3007. PMID:11406576 doi:10.1093/emboj/20.12.2995
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