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Structural basis for SHOC2 modulation of RAS signalling.

Nicholas P D Liau1, Matthew C Johnson1, Saeed Izadi2

  • 1Department of Structural Biology, Genentech, South San Francisco, CA, USA.

Nature
|June 29, 2022
PubMed
Summary
This summary is machine-generated.

The RAS-RAF pathway, crucial in cancer, is better understood through the SHOC2-PP1C-RAS complex structure. This reveals how SHOC2 scaffolds RAS and PP1C to activate RAF, offering new therapeutic targets.

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Area of Science:

  • Molecular biology
  • Structural biology
  • Cancer research

Background:

  • The RAS-RAF pathway is frequently dysregulated in human cancers.
  • Mechanisms of RAF kinase dimerization and activation are not fully understood.
  • 14-3-3 protein stabilizes RAF conformations, but PP1C is needed for dephosphorylation prior to dimerization.

Purpose of the Study:

  • To elucidate the structure of the SHOC2-PP1C-RAS complex.
  • To understand the role of SHOC2 as a scaffolding protein in RAF activation.
  • To identify how RAS isoforms and SHOC2 influence PP1C specificity for RAF.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was used to determine the structure of the SHOC2-PP1C-MRAS complex.
  • Analysis of GTP dependence and RAS isoform preference for complex formation.
  • Investigation of disease-relevant mutations' impact on complex assembly.

Main Results:

  • A tripartite molecular architecture of the SHOC2-PP1C-MRAS complex was revealed at 3 Å resolution.
  • SHOC2 acts as a scaffold, bringing PP1C and MRAS together.
  • The study demonstrated GTP dependence of RAS isoforms and identified SHOC2 and RAS as drivers of PP1C specificity for RAF NTpS.

Conclusions:

  • The structure provides insights into the molecular mechanisms of RAF activation.
  • Disease-associated mutations can disrupt complex assembly.
  • The findings suggest a requirement for two RAS molecules for RAF activation and open avenues for targeted inhibitor development.