7txh: Difference between revisions
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==== | ==Human MRas Q71R in complex with human Shoc2 LRR domain M173I and human PP1Ca== | ||
<StructureSection load='7txh' size='340' side='right'caption='[[7txh]]' scene=''> | <StructureSection load='7txh' size='340' side='right'caption='[[7txh]], [[Resolution|resolution]] 1.95Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[7txh]] is a 6 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=7TXH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TXH FirstGlance]. <br> | ||
</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=7txh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7txh OCA], [https://pdbe.org/7txh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7txh RCSB], [https://www.ebi.ac.uk/pdbsum/7txh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7txh ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=7txh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7txh OCA], [https://pdbe.org/7txh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7txh RCSB], [https://www.ebi.ac.uk/pdbsum/7txh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7txh ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[[https://www.uniprot.org/uniprot/RASM_HUMAN RASM_HUMAN]] Noonan syndrome. The disease is caused by variants affecting the gene represented in this entry. | |||
== Function == | |||
[[https://www.uniprot.org/uniprot/RASM_HUMAN RASM_HUMAN]] Serves as an important signal transducer for a novel upstream stimuli in controlling cell proliferation. Activates the MAP kinase pathway.<ref>PMID:16630891</ref> <ref>PMID:28289718</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
RAS-MAPK signaling is fundamental for cell proliferation and altered in most human cancers(1-3). However, our mechanistic understanding of how RAS signals through RAF is still incomplete. While studies revealed snapshots for autoinhibited and active RAF-MEK1-14-3-3 complexes(4), the intermediate steps leading to RAF activation remain unclear. The MRAS-SHOC2-PP1c holophosphatase de-phosphorylates RAF on Serine 259 resulting in 14-3-3 partial displacement and RAF-RAS association(3,5,6). MRAS, SHOC2 and PP1C are mutated in Rasopathies, developmental syndromes caused by aberrant MAPK pathway activation(6-14) and SHOC2 itself has emerged as potential target in RTK-RAS driven tumors(15-18). Despite its importance, structural understanding of the SHOC2 holophosphatase is lacking. Here we reveal a 1.95 A X-ray crystal structure of the MRAS-SHOC2-PP1C complex. SHOC2 bridges PP1C and MRAS via its concave surface and enables reciprocal interactions between all three subunits. Biophysical characterization indicates a cooperative assembly driven by the MRAS GTP-bound active state, an observation extendible to other RAS isoforms. Our findings support the concept of a RAS-driven and multi-molecular model for RAF activation in which individual RAS-GTP molecules recruit RAF-14-3-3 and SHOC2-PP1C to produce downstream pathway activation. Importantly, we find that Rasopathy and cancer mutations reside at protein-protein interfaces within the holophosphatase, resulting in enhancing affinities and function. Collectively our findings shed light on a fundamental mechanism of RAS biology and on mechanisms for clinically observed enhanced RAS-MAPK signaling, thus providing the structural basis for therapeutic interventions. | |||
Structure of the MRAS-SHOC2-PP1C phosphatase complex.,Hauseman ZJ, Fodor M, Dhembi A, Viscomi J, Egli D, Bleu M, Katz S, Park E, Jang DM, Porter KA, Meili F, Guo H, Kerr G, Molle S, Velez-Vega C, Beyer KS, Galli GG, Maira SM, Stams T, Clark K, Eck MJ, Tordella L, Thoma CR, King DA Nature. 2022 Jul 13. pii: 10.1038/s41586-022-05086-1. doi:, 10.1038/s41586-022-05086-1. PMID:35830882<ref>PMID:35830882</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7txh" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Clark K]] | ||
[[Category: Dhembi A]] | |||
[[Category: Fodor M]] | |||
[[Category: Hauseman ZJ]] | |||
[[Category: King DA]] | |||
[[Category: Viscomi J]] | |||
Revision as of 10:55, 21 September 2022
Human MRas Q71R in complex with human Shoc2 LRR domain M173I and human PP1CaHuman MRas Q71R in complex with human Shoc2 LRR domain M173I and human PP1Ca
Structural highlights
Disease[RASM_HUMAN] Noonan syndrome. The disease is caused by variants affecting the gene represented in this entry. Function[RASM_HUMAN] Serves as an important signal transducer for a novel upstream stimuli in controlling cell proliferation. Activates the MAP kinase pathway.[1] [2] Publication Abstract from PubMedRAS-MAPK signaling is fundamental for cell proliferation and altered in most human cancers(1-3). However, our mechanistic understanding of how RAS signals through RAF is still incomplete. While studies revealed snapshots for autoinhibited and active RAF-MEK1-14-3-3 complexes(4), the intermediate steps leading to RAF activation remain unclear. The MRAS-SHOC2-PP1c holophosphatase de-phosphorylates RAF on Serine 259 resulting in 14-3-3 partial displacement and RAF-RAS association(3,5,6). MRAS, SHOC2 and PP1C are mutated in Rasopathies, developmental syndromes caused by aberrant MAPK pathway activation(6-14) and SHOC2 itself has emerged as potential target in RTK-RAS driven tumors(15-18). Despite its importance, structural understanding of the SHOC2 holophosphatase is lacking. Here we reveal a 1.95 A X-ray crystal structure of the MRAS-SHOC2-PP1C complex. SHOC2 bridges PP1C and MRAS via its concave surface and enables reciprocal interactions between all three subunits. Biophysical characterization indicates a cooperative assembly driven by the MRAS GTP-bound active state, an observation extendible to other RAS isoforms. Our findings support the concept of a RAS-driven and multi-molecular model for RAF activation in which individual RAS-GTP molecules recruit RAF-14-3-3 and SHOC2-PP1C to produce downstream pathway activation. Importantly, we find that Rasopathy and cancer mutations reside at protein-protein interfaces within the holophosphatase, resulting in enhancing affinities and function. Collectively our findings shed light on a fundamental mechanism of RAS biology and on mechanisms for clinically observed enhanced RAS-MAPK signaling, thus providing the structural basis for therapeutic interventions. Structure of the MRAS-SHOC2-PP1C phosphatase complex.,Hauseman ZJ, Fodor M, Dhembi A, Viscomi J, Egli D, Bleu M, Katz S, Park E, Jang DM, Porter KA, Meili F, Guo H, Kerr G, Molle S, Velez-Vega C, Beyer KS, Galli GG, Maira SM, Stams T, Clark K, Eck MJ, Tordella L, Thoma CR, King DA Nature. 2022 Jul 13. pii: 10.1038/s41586-022-05086-1. doi:, 10.1038/s41586-022-05086-1. PMID:35830882[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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