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Conformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis

Author

Listed:
  • Sarah E. Garnish

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Yanxiang Meng

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Akiko Koide

    (New York University Langone Health
    New York University Grossman School of Medicine)

  • Jarrod J. Sandow

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Eric Denbaum

    (New York University Langone Health)

  • Annette V. Jacobsen

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Wayland Yeung

    (University of Georgia)

  • Andre L. Samson

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Christopher R. Horne

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Cheree Fitzgibbon

    (Walter and Eliza Hall Institute of Medical Research)

  • Samuel N. Young

    (Walter and Eliza Hall Institute of Medical Research)

  • Phoebe P. C. Smith

    (Walter and Eliza Hall Institute of Medical Research)

  • Andrew I. Webb

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Emma J. Petrie

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Joanne M. Hildebrand

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Natarajan Kannan

    (University of Georgia
    University of Georgia)

  • Peter E. Czabotar

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Shohei Koide

    (New York University Langone Health
    New York University Grossman School of Medicine)

  • James M. Murphy

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

Abstract

Phosphorylation of the MLKL pseudokinase by the RIPK3 kinase leads to MLKL oligomerization, translocation to, and permeabilization of, the plasma membrane to induce necroptotic cell death. The precise choreography of MLKL activation remains incompletely understood. Here, we report Monobodies, synthetic binding proteins, that bind the pseudokinase domain of MLKL within human cells and their crystal structures in complex with the human MLKL pseudokinase domain. While Monobody-32 constitutively binds the MLKL hinge region, Monobody-27 binds MLKL via an epitope that overlaps the RIPK3 binding site and is only exposed after phosphorylated MLKL disengages from RIPK3 following necroptotic stimulation. The crystal structures identified two distinct conformations of the MLKL pseudokinase domain, supporting the idea that a conformational transition accompanies MLKL disengagement from RIPK3. These studies provide further evidence that MLKL undergoes a large conformational change upon activation, and identify MLKL disengagement from RIPK3 as a key regulatory step in the necroptosis pathway.

Suggested Citation

  • Sarah E. Garnish & Yanxiang Meng & Akiko Koide & Jarrod J. Sandow & Eric Denbaum & Annette V. Jacobsen & Wayland Yeung & Andre L. Samson & Christopher R. Horne & Cheree Fitzgibbon & Samuel N. Young & , 2021. "Conformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22400-z
    DOI: 10.1038/s41467-021-22400-z
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    Cited by:

    1. Yanxiang Meng & Katherine A. Davies & Cheree Fitzgibbon & Samuel N. Young & Sarah E. Garnish & Christopher R. Horne & Cindy Luo & Jean-Marc Garnier & Lung-Yu Liang & Angus D. Cowan & Andre L. Samson &, 2021. "Human RIPK3 maintains MLKL in an inactive conformation prior to cell death by necroptosis," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Sarah E. Garnish & Katherine R. Martin & Maria Kauppi & Victoria E. Jackson & Rebecca Ambrose & Vik Ven Eng & Shene Chiou & Yanxiang Meng & Daniel Frank & Emma C. Tovey Crutchfield & Komal M. Patel & , 2023. "A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Yanxiang Meng & Sarah E. Garnish & Katherine A. Davies & Katrina A. Black & Andrew P. Leis & Christopher R. Horne & Joanne M. Hildebrand & Hanadi Hoblos & Cheree Fitzgibbon & Samuel N. Young & Toby Di, 2023. "Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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