Structure–function analysis of the SHOC2–MRAS–PP1C holophosphatase complex

Jason J. Kwon, Behnoush Hajian, Yuemin Bian, Lucy C. Young, Alvaro J. Amor, James R. Fuller, Cara V. Fraley, Abbey M. Sykes, Jonathan So, Joshua Pan, Laura Baker, Sun Joo Lee, Douglas B. Wheeler, David L. Mayhew, Nicole S. Persky, Xiaoping Yang, David E. Root, Anthony M. Barsotti, Andrew W. Stamford, Charles K. Perry, Alex Burgin, Frank McCormick, Christopher T. Lemke (), William C. Hahn () and Andrew J. Aguirre ()
Additional contact information
Jason J. Kwon: Broad Institute of MIT and Harvard
Behnoush Hajian: Broad Institute of MIT and Harvard
Yuemin Bian: Broad Institute of MIT and Harvard
Lucy C. Young: University of California San Francisco
Alvaro J. Amor: Broad Institute of MIT and Harvard
James R. Fuller: Helix Biostructures
Cara V. Fraley: Broad Institute of MIT and Harvard
Abbey M. Sykes: Harvard Medical School
Jonathan So: Broad Institute of MIT and Harvard
Joshua Pan: Broad Institute of MIT and Harvard
Laura Baker: Broad Institute of MIT and Harvard
Sun Joo Lee: Broad Institute of MIT and Harvard
Douglas B. Wheeler: Broad Institute of MIT and Harvard
David L. Mayhew: Broad Institute of MIT and Harvard
Nicole S. Persky: Broad Institute of MIT and Harvard
Xiaoping Yang: Broad Institute of MIT and Harvard
David E. Root: Broad Institute of MIT and Harvard
Anthony M. Barsotti: Deerfield Management
Andrew W. Stamford: Deerfield Management
Charles K. Perry: Broad Institute of MIT and Harvard
Alex Burgin: Broad Institute of MIT and Harvard
Frank McCormick: University of California San Francisco
Christopher T. Lemke: Broad Institute of MIT and Harvard
William C. Hahn: Broad Institute of MIT and Harvard
Andrew J. Aguirre: Broad Institute of MIT and Harvard

Nature, 2022, vol. 609, issue 7926, 408-415

Abstract: Abstract Receptor tyrosine kinase (RTK)–RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2–MRAS–PP1C holophosphatase complex functions as a key regulator of RTK–RAS signalling by removing an inhibitory phosphorylation event on the RAF family of proteins to potentiate MAPK signalling1. SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations in this complex result in congenital RASopathy syndromes2–5. However, the structure and assembly of this complex are poorly understood. Here we use cryo-electron microscopy to resolve the structure of the SHOC2–MRAS–PP1C complex. We define the biophysical principles of holoenzyme interactions, elucidate the assembly order of the complex, and systematically interrogate the functional consequence of nearly all of the possible missense variants of SHOC2 through deep mutational scanning. We show that SHOC2 binds PP1C and MRAS through the concave surface of the leucine-rich repeat region and further engages PP1C through the N-terminal disordered region that contains a cryptic RVXF motif. Complex formation is initially mediated by interactions between SHOC2 and PP1C and is stabilized by the binding of GTP-loaded MRAS. These observations explain how mutant versions of SHOC2 in RASopathies and cancer stabilize the interactions of complex members to enhance holophosphatase activity. Together, this integrative structure–function model comprehensively defines key binding interactions within the SHOC2–MRAS–PP1C holophosphatase complex and will inform therapeutic development .

Date: 2022
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DOI: 10.1038/s41586-022-04928-2

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