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KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation

Year: 2021
Type: article
Abstract: The first step of RAF activation involves binding to active RAS, resulting in the recruitment of RAF to the plasma membrane. To understand the molecular details of RAS-RAF interaction, we present crystal structures of wild-type and oncogenic mutants of KRAS complexed with the RAS-binding domain (RBD) and the membrane-interacting cysteine-rich domain (CRD) from the N-terminal regulatory region of RAF1. Our structures reveal that RBD and CRD interact with each other to form one structural entity in which both RBD and CRD interact extensively with KRAS. Mutations at the KRAS-CRD interface result in a significant reduction in RAF1 activation despite only a modest decrease in binding affinity. Combining our structures and published data, we provide a model of RAS-RAF complexation at the membrane, and molecular insights into RAS-RAF interaction during the process of RAS-mediated RAF activation.
DOI: 10.1038/s41467-021-21422-x
Authors: Timothy H. Tran, Albert H. Chan, Lucy C. Young, Lakshman Bindu, Chris Neale, Simon Messing, Srisathiyanarayanan Dharmaiah, Troy Taylor, John-Paul Denson, Dominic Esposito, Dwight V. Nissley, Andrew G. Stephen, Frank McCormick, Dhirendra K. Simanshu
Institutions: Frederick National Laboratory for Cancer Research, National Cancer Institute, Leidos Biomedical Research Inc. (United States), University of California, San Francisco, UCSF Helen Diller Family Comprehensive Cancer Center, Los Alamos National Laboratory
Language: English
Open Access status: gold
Estimated APC paid: $5,560
Funders: U.S. Department of Energy, U.S. Department of Health and Human Services, Frederick National Laboratory for Cancer Research, National Institutes of Health, Office of Science, National Cancer Institute, National Institute of General Medical Sciences, Office of Research Infrastructure Programs, National Institutes of Health, Argonne National Laboratory
Awards: G102163711, G107546177, G1313983767, G1386414003, G1664757510, G1851145110, G2287611682, G262962599, G2784524989, G2849897711, G3075337988, G3152346458, G33335446, G3465606404, G3503792436, G386607036, G3924411600, G409777406, G4155925329, G4429385918, G4585269469, G498139845, G4988656331, G5242274761, Pixel Array Detector for Macromolecular Crystallography, G5607048534, G5888954722, G6227691328, G6848031779, G6918803902, G78868261, G9000051782, NE-CAT: A Resource for Advanced Macromolecular Crystallography, G969889393, G993149817
OpenAlex ID: W3131852822
FWCI: 12
Cites: 57
Cited by: 245
Related to: 10