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

Autor:	Ngo VA; Advanced Computing for Life Sciences and Engineering, Science Engagement Section, Computing and Computational Sciences, National Center for Computational Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee. Electronic address: ngoav@ornl.gov.
Jazyk:	angličtina
Zdroj:	Biophysical journal [Biophys J] 2024 Aug 20; Vol. 123 (16), pp. 2623-2637. Date of Electronic Publication: 2024 Jun 29.
DOI:	10.1016/j.bpj.2024.06.028
Abstrakt:	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. We propose a model of Raf-heterodimer/KRas-dimer as a signalosome based on the dynamics of the full-length CRaf. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Biophysical Society. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu