Structure of the MRAS–SHOC2–PP1C phosphatase complex

Zachary J. Hauseman (), Michelle Fodor, Anxhela Dhembi, Jessica Viscomi, David Egli, Melusine Bleu, Stephanie Katz, Eunyoung Park, Dong Man Jang, Kathryn A. Porter, Fabian Meili, Hongqiu Guo, Grainne Kerr, Sandra Mollé, Camilo Velez-Vega, Kim S. Beyer, Giorgio G. Galli, Saveur-Michel Maira, Travis Stams, Kirk Clark, Michael J. Eck, Luca Tordella (), Claudio R. Thoma () and Daniel A. King ()
Additional contact information
Zachary J. Hauseman: Novartis Institutes for BioMedical Research
Michelle Fodor: Novartis Institutes for BioMedical Research
Anxhela Dhembi: Novartis Institutes for BioMedical Research
Jessica Viscomi: Novartis Institutes for BioMedical Research
David Egli: Novartis Institutes for BioMedical Research
Melusine Bleu: Novartis Institutes for BioMedical Research
Stephanie Katz: Novartis Institutes for BioMedical Research
Eunyoung Park: Harvard Medical School
Dong Man Jang: Harvard Medical School
Kathryn A. Porter: Novartis Institutes for BioMedical Research
Fabian Meili: Novartis Institutes for BioMedical Research
Hongqiu Guo: Novartis Institutes for BioMedical Research
Grainne Kerr: Novartis Institutes for BioMedical Research
Sandra Mollé: Novartis Institutes for BioMedical Research
Camilo Velez-Vega: Novartis Institutes for BioMedical Research
Kim S. Beyer: Novartis Institutes for BioMedical Research
Giorgio G. Galli: Novartis Institutes for BioMedical Research
Saveur-Michel Maira: Novartis Institutes for BioMedical Research
Travis Stams: Novartis Institutes for BioMedical Research
Kirk Clark: Novartis Institutes for BioMedical Research
Michael J. Eck: Harvard Medical School
Luca Tordella: Novartis Institutes for BioMedical Research
Claudio R. Thoma: Novartis Institutes for BioMedical Research
Daniel A. King: Novartis Institutes for BioMedical Research

Nature, 2022, vol. 609, issue 7926, 416-423

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-022-05086-1

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