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TitleStructural basis for SHOC2 modulation of RAS signalling.
Journal, issue, pagesNature, Vol. 609, Issue 7926, Page 400-407, Year 2022
Publish dateJun 29, 2022
AuthorsNicholas P D Liau / Matthew C Johnson / Saeed Izadi / Luca Gerosa / Michal Hammel / John M Bruning / Timothy J Wendorff / Wilson Phung / Sarah G Hymowitz / Jawahar Sudhamsu /
PubMed AbstractThe 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 ...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.
External linksNature / PubMed:35768504 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.95 - 3.19 Å
Structure data

25044

7sd0

EMDB-25044, PDB-7sd0:
Cryo-EM structure of the SHOC2:PP1C:MRAS complex
Method: EM (single particle) / Resolution: 2.95 Å

PDB-7sd1:
Crystal structure of SHOC2
Method: X-RAY DIFFRACTION / Resolution: 3.19 Å

Chemicals

ChemComp-GCP:
PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER / GMP-PCP, energy-carrying molecule analogue*YM

ChemComp-MG:
Unknown entry

ChemComp-MN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / Phosphatase / leucine rich repeat / RAF / complex / PP1C / RAS / Scaffold

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