Insight into molecular basis and dynamics of full-length CRaf kinase in cellular signaling mechanisms

Ngo, Van A.

doi:10.1016/j.bpj.2024.06.028

Insight into molecular basis and dynamics of full-length CRaf kinase in cellular signaling mechanisms

Journal Article · Sat Jun 29 00:00:00 EDT 2024 · Biophysical Journal

DOI:https://doi.org/10.1016/j.bpj.2024.06.028· OSTI ID:2406782

^[1]

Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Raf kinases play key roles in signal transduction in cells for regulating proliferation, differentiation, and survival. Despite decades of research into functions and dynamics of Raf kinases with respect to other cytosolic proteins, understanding Raf kinases is limited by the lack of their full-length structures at the atomic resolution. Here, we present the first model of the full-length CRaf kinase obtained from artificial intelligence/machine learning algorithms with a converging ensemble of structures simulated by large-scale temperature replica exchange simulations. Our model is validated by comparing simulated structures with the latest cryo-EM structure detailing close contacts among three key domains and regions of the CRaf. Our simulations identify potentially new epitopes of intramolecule interactions within the CRaf and reveal a dynamical nature of CRaf kinases, in which the three domains can move back and forth relative to each other for regulatory dynamics. The dynamic conformations are then used in a docking algorithm to shed insight into the paradoxical effect caused by vemurafenib in comparison with a paradox breaker PLX7904. In this study, we propose a model of Raf-heterodimer/KRas-dimer as a signalosome based on the dynamics of the full-length CRaf.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 2406782

Journal Information:: Biophysical Journal, Journal Name: Biophysical Journal Vol. 123; ISSN 0006-3495

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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