7SD0

Cryo-EM structure of the SHOC2:PP1C:MRAS complex

7SD0 の概要

• エントリーDOI: 10.2210/pdb7sd0/pdb
• EMDBエントリー: 25044
• 分子名称: Leucine-rich repeat protein SHOC-2, Ras-related protein M-Ras, Serine/threonine-protein phosphatase PP1-gamma catalytic subunit, ... (6 entities in total)
• 機能のキーワード: phosphatase, leucine rich repeat, raf, complex, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 127015.88

構造登録者

Liau, N.P.D.,Johnson, M.C.,Hymowitz, S.G.,Sudhamsu, J. (登録日: 2021-09-29, 公開日: 2022-04-20, 最終更新日: 2023-11-29)

主引用文献

Liau, N.P.D.,Johnson, M.C.,Izadi, S.,Gerosa, L.,Hammel, M.,Bruning, J.M.,Wendorff, T.J.,Phung, W.,Hymowitz, S.G.,Sudhamsu, J.
Structural basis for SHOC2 modulation of RAS signalling.
Nature, 609:400-407, 2022

PubMed Abstract: The RAS-RAF pathway is one of the most commonly dysregulated in human cancers. Despite decades of study, understanding of the molecular mechanisms underlying dimerization and activation of the kinase RAF remains limited. Recent structures of inactive RAF monomer and active RAF dimer bound to 14-3-3 have revealed the mechanisms by which 14-3-3 stabilizes both RAF conformations via specific phosphoserine residues. Prior to RAF dimerization, the protein phosphatase 1 catalytic subunit (PP1C) must dephosphorylate the N-terminal phosphoserine (NTpS) of RAF to relieve inhibition by 14-3-3, although PP1C in isolation lacks intrinsic substrate selectivity. SHOC2 is as an essential scaffolding protein that engages both PP1C and RAS to dephosphorylate RAF NTpS, but the structure of SHOC2 and the architecture of the presumptive SHOC2-PP1C-RAS complex remain unknown. Here we present a cryo-electron microscopy structure of the SHOC2-PP1C-MRAS complex to an overall resolution of 3 Å, revealing a tripartite molecular architecture in which a crescent-shaped SHOC2 acts as a cradle and brings together PP1C and MRAS. Our work demonstrates the GTP dependence of multiple RAS isoforms for complex formation, delineates the RAS-isoform preference for complex assembly, and uncovers how the SHOC2 scaffold and RAS collectively drive specificity of PP1C for RAF NTpS. Our data indicate that disease-relevant mutations affect complex assembly, reveal the simultaneous requirement of two RAS molecules for RAF activation, and establish rational avenues for discovery of new classes of inhibitors to target this pathway.

PubMed: 35768504
DOI: 10.1038/s41586-022-04838-3

実験手法

ELECTRON MICROSCOPY (2.95 Å)