A structural model of a Ras–Raf signalosome

Venkatesh P. Mysore, Zhi Wei Zhou, Chiara Ambrogio, Lianbo Li, Jonas N. Kapp, Chunya Lu, Qi Wang, Maxwell R. Tucker, Jeffrey J. Okoro, Gabriela Nagy-Davidescu, Xiaochen Bai, Andreas Plückthun, Pasi A. Jänne, Kenneth D. Westover, Yibing Shan, David E. Shaw

Research output: Contribution to journalArticlepeer-review

Abstract

The protein K-Ras functions as a molecular switch in signaling pathways regulating cell growth. In the human mitogen-activated protein kinase (MAPK) pathway, which is implicated in many cancers, multiple K-Ras proteins are thought to assemble at the cell membrane with Ras effector proteins from the Raf family. Here we propose an atomistic structural model for such an assembly. Our starting point was an asymmetric guanosine triphosphate-mediated K-Ras dimer model, which we generated using unbiased molecular dynamics simulations and verified with mutagenesis experiments. Adding further K-Ras monomers in a head-to-tail fashion led to a compact helical assembly, a model we validated using electron microscopy and cell-based experiments. This assembly stabilizes K-Ras in its active state and presents composite interfaces to facilitate Raf binding. Guided by existing experimental data, we then positioned C-Raf, the downstream kinase MEK1 and accessory proteins (Galectin-3 and 14-3-3σ) on and around the helical assembly. The resulting Ras–Raf signalosome model offers an explanation for a large body of data on MAPK signaling.

Original languageEnglish (US)
Pages (from-to)847-857
Number of pages11
JournalNature Structural and Molecular Biology
Volume28
Issue number10
DOIs
StatePublished - Oct 2021

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Fingerprint

Dive into the research topics of 'A structural model of a Ras–Raf signalosome'. Together they form a unique fingerprint.

Cite this