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

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 () and Dhirendra K. Simanshu ()
Additional contact information
Timothy H. Tran: Leidos Biomedical Research, Inc.
Albert H. Chan: Leidos Biomedical Research, Inc.
Lucy C. Young: University of California
Lakshman Bindu: Leidos Biomedical Research, Inc.
Chris Neale: Los Alamos National Laboratory
Simon Messing: Leidos Biomedical Research, Inc.
Srisathiyanarayanan Dharmaiah: Leidos Biomedical Research, Inc.
Troy Taylor: Leidos Biomedical Research, Inc.
John-Paul Denson: Leidos Biomedical Research, Inc.
Dominic Esposito: Leidos Biomedical Research, Inc.
Dwight V. Nissley: Leidos Biomedical Research, Inc.
Andrew G. Stephen: Leidos Biomedical Research, Inc.
Frank McCormick: Leidos Biomedical Research, Inc.
Dhirendra K. Simanshu: Leidos Biomedical Research, Inc.

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21422-x

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