Structure of the MRAS-SHOC2-PP1C phosphatase complex

Nature. 2022 Sep;609(7926):416-423. doi: 10.1038/s41586-022-05086-1. Epub 2022 Jul 13.


RAS-MAPK signalling is fundamental for cell proliferation and is altered in most human cancers1-3. 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 complexes4, 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 association3,5,6. MRAS, SHOC2 and PP1C are mutated in rasopathies-developmental syndromes caused by aberrant MAPK pathway activation6-14-and SHOC2 itself has emerged as potential target in receptor tyrosine kinase (RTK)-RAS-driven tumours15-18. 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.

MeSH terms

  • 14-3-3 Proteins
  • Crystallography, X-Ray*
  • Guanosine Triphosphate / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins* / chemistry
  • Intracellular Signaling Peptides and Proteins* / metabolism
  • MAP Kinase Signaling System
  • Multiprotein Complexes* / chemistry
  • Mutation
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Protein Phosphatase 1* / chemistry
  • Protein Phosphatase 1* / genetics
  • Protein Phosphatase 1* / metabolism
  • Protein Subunits / chemistry
  • Protein Subunits / metabolism
  • raf Kinases
  • ras Proteins* / chemistry
  • ras Proteins* / metabolism


  • 14-3-3 Proteins
  • Intracellular Signaling Peptides and Proteins
  • MRAS protein, human
  • Multiprotein Complexes
  • Protein Isoforms
  • Protein Subunits
  • SHOC2 protein, human
  • Guanosine Triphosphate
  • raf Kinases
  • Protein Phosphatase 1
  • ras Proteins