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

Tran, Timothy H.; Chan, Albert H.; Young, Lucy C.; Bindu, Lakshman; Neale, Christopher Andrew; Messing, Simon; Dharmaiah, Srisathiyanarayanan; Taylor, Troy; Denson, John-Paul; Esposito, Dominic; Nissley, Dwight V.; Stephen, Andrew G.; McCormick, Frank; Simanshu, Dhirendra K.

doi:10.1038/s41467-021-21422-x

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

Journal Article · Fri Feb 19 00:00:00 EST 2021 · Nature Communications

DOI:https://doi.org/10.1038/s41467-021-21422-x· OSTI ID:1767216

Tran, Timothy H. ^[1]; Chan, Albert H. ^[1]; Young, Lucy C. ^[2]; Bindu, Lakshman ^[1];

^[3]; Messing, Simon ^[1];

^[1]; Taylor, Troy ^[1]; Denson, John-Paul ^[1];

^[1];

^[1]; Stephen, Andrew G. ^[1];

^[4];

^[1]

Leidos Biomedical Research, Inc., Frederick, MD (United States). Frederick National Lab. for Cancer Research
Univ. of California, San Francisco, CA (United States)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Leidos Biomedical Research, Inc., Frederick, MD (United States). Frederick National Lab. for Cancer Research; Univ. of California, San Francisco, CA (United States)

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.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS); Office of Research Infrastructure Programs (ORIP); USDOE Office of Science (SC); National Cancer Institute (NCI)

Grant/Contract Number:: AC02-06CH11357; HHSN261200800001E; P30 GM124165; S10OD021527; 89233218CNA000001

OSTI ID:: 1767216

Alternate ID(s):: OSTI ID: 1804340

Report Number(s):: LA-UR-20-24476; APS_261366

Journal Information:: Nature Communications, Vol. 12, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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