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Nature

Resumen/Descripción – provisto por la editorial en inglés

Nature is a weekly international journal publishing the finest peer-reviewed research in all fields of science and technology on the basis of its originality, importance, interdisciplinary interest, timeliness, accessibility, elegance and surprising conclusions. Nature also provides rapid, authoritative, insightful and arresting news and interpretation of topical and coming trends affecting science, scientists and the wider public.

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Tipo de recurso:

revistas

ISSN impreso

0028-0836

ISSN electrónico

1476-4687

Editor responsable

Springer Nature

País de edición

Reino Unido

Fecha de publicación

1869-

Cobertura temática

Ciencias naturales

Ingeniería y tecnología

Ciencias médicas y de la salud

Ciencias agrícolas y veterinarias

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doi: 10.1038/s41586-022-04838-3

Structural basis for SHOC2 modulation of RAS signalling

Nicholas P. D. Liau; Matthew C. Johnson; Saeed Izadi; Luca Gerosa; Michal Hammel; John M. Bruning; Timothy J. Wendorff; Wilson Phung; Sarah G. Hymowitz; Jawahar Sudhamsu

<jats:title>Abstract</jats:title><jats:p>The RASâ€“RAF pathway is one of the most commonly dysregulated in human cancers<jats:sup>1â€“3</jats:sup>. Despite decades of study, understanding of the molecular mechanisms underlying dimerization and activation<jats:sup>4</jats:sup> of the kinase RAF remains limited. Recent structures of inactive RAF monomer<jats:sup>5</jats:sup> and active RAF dimer<jats:sup>5â€“8</jats:sup> bound to 14-3-3<jats:sup>9,10</jats:sup> 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 RAF<jats:sup>11</jats:sup> 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 NTpS<jats:sup>11â€“13</jats:sup>, but the structure of SHOC2 and the architecture of the presumptive SHOC2â€“PP1Câ€“RAS complex remain unknown. Here we present a cryo-electron microscopy structure of the SHOC2â€“PP1Câ€“MRAS complex to an overall resolution of 3â€‰Ã…, 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.</jats:p>

Palabras clave: Multidisciplinary.

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