7TXH

Human MRas Q71R in complex with human Shoc2 LRR domain M173I and human PP1Ca

7TXH の概要

• エントリーDOI: 10.2210/pdb7txh/pdb
• 分子名称: Ras-related protein M-Ras, Leucine-rich repeat protein SHOC-2, Serine/threonine-protein phosphatase PP1-alpha catalytic subunit, ... (9 entities in total)
• 機能のキーワード: ras, pp1, shoc2, lrr, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 225667.97

構造登録者

Hauseman, Z.J.,Viscomi, J.,Dhembi, A.,Clark, K.,King, D.A.,Fodor, M. (登録日: 2022-02-09, 公開日: 2022-06-22, 最終更新日: 2023-10-18)

主引用文献

Hauseman, Z.J.,Fodor, M.,Dhembi, A.,Viscomi, J.,Egli, D.,Bleu, M.,Katz, S.,Park, E.,Jang, D.M.,Porter, K.A.,Meili, F.,Guo, H.,Kerr, G.,Molle, S.,Velez-Vega, C.,Beyer, K.S.,Galli, G.G.,Maira, S.M.,Stams, T.,Clark, K.,Eck, M.J.,Tordella, L.,Thoma, C.R.,King, D.A.
Structure of the MRAS-SHOC2-PP1C phosphatase complex.
Nature, 609:416-423, 2022

PubMed Abstract: RAS-MAPK signalling is fundamental for cell proliferation and is altered in most human cancers. However, our mechanistic understanding of how RAS signals through RAF is still incomplete. Although studies revealed snapshots for autoinhibited and active RAF-MEK1-14-3-3 complexes, the intermediate steps that lead to RAF activation remain unclear. The MRAS-SHOC2-PP1C holophosphatase dephosphorylates RAF at serine 259, resulting in the partial displacement of 14-3-3 and RAF-RAS association. MRAS, SHOC2 and PP1C are mutated in rasopathies-developmental syndromes caused by aberrant MAPK pathway activation-and SHOC2 itself has emerged as potential target in receptor tyrosine kinase (RTK)-RAS-driven tumours. Despite its importance, structural understanding of the SHOC2 holophosphatase is lacking. Here we determine, using X-ray crystallography, the structure of the MRAS-SHOC2-PP1C complex. SHOC2 bridges PP1C and MRAS through 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 that is 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 enhanced affinities and function. Collectively, our findings shed light on a fundamental mechanism of RAS biology and on mechanisms of clinically observed enhanced RAS-MAPK signalling, therefore providing the structural basis for therapeutic interventions.

PubMed: 35830882
DOI: 10.1038/s41586-022-05086-1

実験手法

X-RAY DIFFRACTION (1.95 Å)