RT Journal Article
SR Electronic
T1 A structural model of a Ras-Raf signalosome
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.15.165266
DO 10.1101/2020.07.15.165266
A1 Venkatesh P. Mysore
A1 Zhi-Wei Zhou
A1 Chiara Ambrogio
A1 Lianbo Li
A1 Jonas N. Kapp
A1 Chunya Lu
A1 Qi Wang
A1 Maxwell R. Tucker
A1 Jeffrey J. Okoro
A1 Gabriela Nagy-Davidescu
A1 Xiaochen Bai
A1 Andreas Plückthun
A1 Pasi A. Jänne
A1 Kenneth D. Westover
A1 Yibing Shan
A1 David E. Shaw
YR 2020
UL http://biorxiv.org/content/early/2020/07/15/2020.07.15.165266.abstract
AB 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 StatementThe authors have declared no competing interest.