Structural basis for SHOC2 modulation of RAS signalling

Nature. 2022 Sep;609(7926):400-407. doi: 10.1038/s41586-022-04838-3. Epub 2022 Jun 29.


The RAS-RAF pathway is one of the most commonly dysregulated in human cancers1-3. Despite decades of study, understanding of the molecular mechanisms underlying dimerization and activation4 of the kinase RAF remains limited. Recent structures of inactive RAF monomer5 and active RAF dimer5-8 bound to 14-3-39,10 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 RAF11 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 NTpS11-13, 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.

MeSH terms

  • Cryoelectron Microscopy
  • Guanosine Triphosphate / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins* / chemistry
  • Intracellular Signaling Peptides and Proteins* / genetics
  • Intracellular Signaling Peptides and Proteins* / metabolism
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Multiprotein Complexes / ultrastructure
  • Mutation
  • Phosphoserine
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Isoforms / ultrastructure
  • Protein Phosphatase 1* / chemistry
  • Protein Phosphatase 1* / genetics
  • Protein Phosphatase 1* / metabolism
  • Protein Phosphatase 1* / ultrastructure
  • Signal Transduction*
  • Substrate Specificity
  • raf Kinases / metabolism
  • ras Proteins* / chemistry
  • ras Proteins* / genetics
  • ras Proteins* / metabolism
  • ras Proteins* / ultrastructure


  • Intracellular Signaling Peptides and Proteins
  • MRAS protein, human
  • Multiprotein Complexes
  • Protein Isoforms
  • SHOC2 protein, human
  • Phosphoserine
  • Guanosine Triphosphate
  • raf Kinases
  • Protein Phosphatase 1
  • ras Proteins