A structural model of a Ras-Raf signalosome
Venkatesh P. Mysore,
Jonas N. Kapp,
Maxwell R. Tucker,
Jeffrey J. Okoro,
Pasi A. Jänne,
Kenneth D. Westover,
David E. Shaw
Posted 15 Jul 2020
bioRxiv DOI: 10.1101/2020.07.15.165266
Posted 15 Jul 2020
The protein K-Ras functions as a molecular switch in signaling pathways regulating cell growth. In the 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, GTP-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 the helical assembly. The resulting Ras-Raf signalosome model offers an explanation for a large body of data on MAPK signaling. ### Competing Interest Statement The authors have declared no competing interest.
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