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

Author

Listed:
  • 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.
    University of California)

  • Dhirendra K. Simanshu

    (Leidos Biomedical Research, Inc.)

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.

Suggested Citation

  • 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 , 2021. "KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21422-x
    DOI: 10.1038/s41467-021-21422-x
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    Cited by:

    1. Brandon M. Murphy & Elizabeth M. Terrell & Venkat R. Chirasani & Tirzah J. Weiss & Rachel E. Lew & Andrea M. Holderbaum & Aastha Dhakal & Valentina Posada & Marie Fort & Michael S. Bodnar & Leiah M. C, 2022. "Enhanced BRAF engagement by NRAS mutants capable of promoting melanoma initiation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Eunyoung Park & Shaun Rawson & Anna Schmoker & Byeong-Won Kim & Sehee Oh & Kangkang Song & Hyesung Jeon & Michael J. Eck, 2023. "Cryo-EM structure of a RAS/RAF recruitment complex," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. Alexander E. Vlahos & Jeewoo Kang & Carlos A. Aldrete & Ronghui Zhu & Lucy S. Chong & Michael B. Elowitz & Xiaojing J. Gao, 2022. "Protease-controlled secretion and display of intercellular signals," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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