7TVF

Crystal structure of the SHOC2-MRAS-PP1CA (SMP) complex to a resolution of 2.17 Angstrom

Summary for 7TVF

• Entry DOI: 10.2210/pdb7tvf/pdb
• Descriptor: Serine/threonine-protein phosphatase PP1-alpha catalytic subunit, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, MAGNESIUM ION, ... (12 entities in total)
• Functional Keywords: oncoprotein phosphatase scaffold protein adaptor ras leucine rich repeat, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 249100.53

Authors

Bonsor, D.A.,Simanshu, D.K. (deposition date: 2022-02-04, release date: 2022-05-04, Last modification date: 2023-10-18)

Primary citation

Bonsor, D.A.,Alexander, P.,Snead, K.,Hartig, N.,Drew, M.,Messing, S.,Finci, L.I.,Nissley, D.V.,McCormick, F.,Esposito, D.,Rodriguez-Viciana, P.,Stephen, A.G.,Simanshu, D.K.
Structure of the SHOC2-MRAS-PP1C complex provides insights into RAF activation and Noonan syndrome.
Nat.Struct.Mol.Biol., 29:966-977, 2022

PubMed Abstract: SHOC2 acts as a strong synthetic lethal interactor with MEK inhibitors in multiple KRAS cancer cell lines. SHOC2 forms a heterotrimeric complex with MRAS and PP1C that is essential for regulating RAF and MAPK-pathway activation by dephosphorylating a specific phosphoserine on RAF kinases. Here we present the high-resolution crystal structure of the SHOC2-MRAS-PP1C (SMP) complex and apo-SHOC2. Our structures reveal that SHOC2, MRAS, and PP1C form a stable ternary complex in which all three proteins synergistically interact with each other. Our results show that dephosphorylation of RAF substrates by PP1C is enhanced upon interacting with SHOC2 and MRAS. The SMP complex forms only when MRAS is in an active state and is dependent on SHOC2 functioning as a scaffolding protein in the complex by bringing PP1C and MRAS together. Our results provide structural insights into the role of the SMP complex in RAF activation and how mutations found in Noonan syndrome enhance complex formation, and reveal new avenues for therapeutic interventions.

PubMed: 36175670
DOI: 10.1038/s41594-022-00841-4

Experimental method

X-RAY DIFFRACTION (2.17 Å)