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| | ==Autoinhibited state of the Ras-specific exchange factor RasGRP1== | | ==Autoinhibited state of the Ras-specific exchange factor RasGRP1== |
| - | <StructureSection load='4l9m' size='340' side='right' caption='[[4l9m]], [[Resolution|resolution]] 3.00Å' scene=''> | + | <StructureSection load='4l9m' size='340' side='right'caption='[[4l9m]], [[Resolution|resolution]] 3.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4l9m]] is a 1 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=4L9M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4L9M FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4l9m]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4L9M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4L9M FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RASGRP1, RASGRP ([http://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'>[https://proteopedia.org/fgij/fg.htm?mol=4l9m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l9m OCA], [https://pdbe.org/4l9m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4l9m RCSB], [https://www.ebi.ac.uk/pdbsum/4l9m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4l9m ProSAT]</span></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=4l9m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4l9m OCA], [http://pdbe.org/4l9m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4l9m RCSB], [http://www.ebi.ac.uk/pdbsum/4l9m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4l9m ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/GRP1_HUMAN GRP1_HUMAN]] Disease susceptibility is associated with variations affecting the gene represented in this entry. Aberrantly spliced isoforms and/or diminished levels of RASGRP1 are found in a cohort of SLE patients raising the possibility that dysregulation of this signaling protein contributes to the development of autoimmunity in a subset of SLE patients. | + | [https://www.uniprot.org/uniprot/GRP1_HUMAN GRP1_HUMAN] Disease susceptibility is associated with variations affecting the gene represented in this entry. Aberrantly spliced isoforms and/or diminished levels of RASGRP1 are found in a cohort of SLE patients raising the possibility that dysregulation of this signaling protein contributes to the development of autoimmunity in a subset of SLE patients. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GRP1_HUMAN GRP1_HUMAN]] Functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP. Activates the Erk/MAP kinase cascade. Couples T-lymphocytes and B-lymphocytes antigen receptors to the activation of Ras. Hence, regulates T-cells and B-cells development, homeostasis and differentiation. Functions also in FcERI-evoked degranulation and cytokine secretion by mast cells, regulating allergic responses. May also function in other cell types differentiation.<ref>PMID:10807788</ref> <ref>PMID:12839994</ref> <ref>PMID:12782630</ref> <ref>PMID:12845332</ref> <ref>PMID:15060167</ref> <ref>PMID:15184873</ref> <ref>PMID:15899849</ref> | + | [https://www.uniprot.org/uniprot/GRP1_HUMAN GRP1_HUMAN] Functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP. Activates the Erk/MAP kinase cascade. Couples T-lymphocytes and B-lymphocytes antigen receptors to the activation of Ras. Hence, regulates T-cells and B-cells development, homeostasis and differentiation. Functions also in FcERI-evoked degranulation and cytokine secretion by mast cells, regulating allergic responses. May also function in other cell types differentiation.<ref>PMID:10807788</ref> <ref>PMID:12839994</ref> <ref>PMID:12782630</ref> <ref>PMID:12845332</ref> <ref>PMID:15060167</ref> <ref>PMID:15184873</ref> <ref>PMID:15899849</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Barros, T]] | + | [[Category: Large Structures]] |
| - | [[Category: Che, Y]] | + | [[Category: Barros T]] |
| - | [[Category: Das, R]] | + | [[Category: Che Y]] |
| - | [[Category: Iwig, J S]] | + | [[Category: Das R]] |
| - | [[Category: Kuriyan, J]] | + | [[Category: Iwig JS]] |
| - | [[Category: Limnander, A]] | + | [[Category: Kuriyan J]] |
| - | [[Category: Pelton, J G]] | + | [[Category: Limnander A]] |
| - | [[Category: Roose, J P]] | + | [[Category: Pelton JG]] |
| - | [[Category: Vercoulen, Y]] | + | [[Category: Roose JP]] |
| - | [[Category: Wemmer, D E]] | + | [[Category: Vercoulen Y]] |
| - | [[Category: Ras nucleotide exchange factor]]
| + | [[Category: Wemmer DE]] |
| - | [[Category: Signaling protein]]
| + | |
| Structural highlights
Disease
GRP1_HUMAN Disease susceptibility is associated with variations affecting the gene represented in this entry. Aberrantly spliced isoforms and/or diminished levels of RASGRP1 are found in a cohort of SLE patients raising the possibility that dysregulation of this signaling protein contributes to the development of autoimmunity in a subset of SLE patients.
Function
GRP1_HUMAN Functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP. Activates the Erk/MAP kinase cascade. Couples T-lymphocytes and B-lymphocytes antigen receptors to the activation of Ras. Hence, regulates T-cells and B-cells development, homeostasis and differentiation. Functions also in FcERI-evoked degranulation and cytokine secretion by mast cells, regulating allergic responses. May also function in other cell types differentiation.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
RasGRP1 and SOS are Ras-specific nucleotide exchange factors that have distinct roles in lymphocyte development. RasGRP1 is important in some cancers and autoimmune diseases but, in contrast to SOS, its regulatory mechanisms are poorly understood. Activating signals lead to the membrane recruitment of RasGRP1 and Ras engagement, but it is unclear how interactions between RasGRP1 and Ras are suppressed in the absence of such signals. We present a crystal structure of a fragment of RasGRP1 in which the Ras-binding site is blocked by an interdomain linker and the membrane-interaction surface of RasGRP1 is hidden within a dimerization interface that may be stabilized by the C-terminal oligomerization domain. NMR data demonstrate that calcium binding to the regulatory module generates substantial conformational changes that are incompatible with the inactive assembly. These features allow RasGRP1 to be maintained in an inactive state that is poised for activation by calcium and membrane-localization signals. DOI:http://dx.doi.org/10.7554/eLife.00813.001.
Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1.,Iwig JS, Vercoulen Y, Das R, Barros T, Limnander A, Che Y, Pelton JG, Wemmer DE, Roose JP, Kuriyan J Elife. 2013 Jul 30;2:e00813. doi: 10.7554/eLife.00813. Print 2013. PMID:23908768[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Ebinu JO, Stang SL, Teixeira C, Bottorff DA, Hooton J, Blumberg PM, Barry M, Bleakley RC, Ostergaard HL, Stone JC. RasGRP links T-cell receptor signaling to Ras. Blood. 2000 May 15;95(10):3199-203. PMID:10807788
- ↑ Caloca MJ, Zugaza JL, Matallanas D, Crespo P, Bustelo XR. Vav mediates Ras stimulation by direct activation of the GDP/GTP exchange factor Ras GRP1. EMBO J. 2003 Jul 1;22(13):3326-36. PMID:12839994 doi:10.1093/emboj/cdg316
- ↑ Caloca MJ, Zugaza JL, Bustelo XR. Exchange factors of the RasGRP family mediate Ras activation in the Golgi. J Biol Chem. 2003 Aug 29;278(35):33465-73. Epub 2003 Jun 2. PMID:12782630 doi:10.1074/jbc.M302807200
- ↑ Bivona TG, Perez De Castro I, Ahearn IM, Grana TM, Chiu VK, Lockyer PJ, Cullen PJ, Pellicer A, Cox AD, Philips MR. Phospholipase Cgamma activates Ras on the Golgi apparatus by means of RasGRP1. Nature. 2003 Aug 7;424(6949):694-8. Epub 2003 Jun 29. PMID:12845332 doi:10.1038/nature01806
- ↑ Perez de Castro I, Bivona TG, Philips MR, Pellicer A. Ras activation in Jurkat T cells following low-grade stimulation of the T-cell receptor is specific to N-Ras and occurs only on the Golgi apparatus. Mol Cell Biol. 2004 Apr;24(8):3485-96. PMID:15060167
- ↑ Zugaza JL, Caloca MJ, Bustelo XR. Inverted signaling hierarchy between RAS and RAC in T-lymphocytes. Oncogene. 2004 Jul 29;23(34):5823-33. PMID:15184873 doi:10.1038/sj.onc.1207768
- ↑ Roose JP, Mollenauer M, Gupta VA, Stone J, Weiss A. A diacylglycerol-protein kinase C-RasGRP1 pathway directs Ras activation upon antigen receptor stimulation of T cells. Mol Cell Biol. 2005 Jun;25(11):4426-41. PMID:15899849 doi:25/11/4426
- ↑ Iwig JS, Vercoulen Y, Das R, Barros T, Limnander A, Che Y, Pelton JG, Wemmer DE, Roose JP, Kuriyan J. Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1. Elife. 2013 Jul 30;2:e00813. doi: 10.7554/eLife.00813. Print 2013. PMID:23908768 doi:10.7554/eLife.00813
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