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Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis

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Listed:
  • Emma J. Petrie

    (The Walter & Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Jarrod J. Sandow

    (The Walter & Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Annette V. Jacobsen

    (The Walter & Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Brian J. Smith

    (LaTrobe University)

  • Michael D. W. Griffin

    (The University of Melbourne, The Bio21 Institute)

  • Isabelle S. Lucet

    (The Walter & Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Weiwen Dai

    (The Walter & Eliza Hall Institute of Medical Research)

  • Samuel N. Young

    (The Walter & Eliza Hall Institute of Medical Research)

  • Maria C. Tanzer

    (The Walter & Eliza Hall Institute of Medical Research
    The University of Melbourne
    Max Planck Institute of Biochemistry)

  • Ahmad Wardak

    (The Walter & Eliza Hall Institute of Medical Research)

  • Lung-Yu Liang

    (The Walter & Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Angus D. Cowan

    (The Walter & Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Joanne M. Hildebrand

    (The Walter & Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Wilhelmus J. A. Kersten

    (The Walter & Eliza Hall Institute of Medical Research)

  • Guillaume Lessene

    (The Walter & Eliza Hall Institute of Medical Research
    The University of Melbourne
    The University of Melbourne)

  • John Silke

    (The Walter & Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Peter E. Czabotar

    (The Walter & Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Andrew I. Webb

    (The Walter & Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • James M. Murphy

    (The Walter & Eliza Hall Institute of Medical Research
    The University of Melbourne)

Abstract

Necroptotic cell death is mediated by the most terminal known effector of the pathway, MLKL. Precisely how phosphorylation of the MLKL pseudokinase domain activation loop by the upstream kinase, RIPK3, induces unmasking of the N-terminal executioner four-helix bundle (4HB) domain of MLKL, higher-order assemblies, and permeabilization of plasma membranes remains poorly understood. Here, we reveal the existence of a basal monomeric MLKL conformer present in human cells prior to exposure to a necroptotic stimulus. Following activation, toggling within the MLKL pseudokinase domain promotes 4HB domain disengagement from the pseudokinase domain αC helix and pseudocatalytic loop, to enable formation of a necroptosis-inducing tetramer. In contrast to mouse MLKL, substitution of RIPK3 substrate sites in the human MLKL pseudokinase domain completely abrogated necroptotic signaling. Therefore, while the pseudokinase domains of mouse and human MLKL function as molecular switches to control MLKL activation, the underlying mechanism differs between species.

Suggested Citation

  • Emma J. Petrie & Jarrod J. Sandow & Annette V. Jacobsen & Brian J. Smith & Michael D. W. Griffin & Isabelle S. Lucet & Weiwen Dai & Samuel N. Young & Maria C. Tanzer & Ahmad Wardak & Lung-Yu Liang & A, 2018. "Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04714-7
    DOI: 10.1038/s41467-018-04714-7
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    Cited by:

    1. Christoph Grohmann & Charlene M. Magtoto & Joel R. Walker & Ngee Kiat Chua & Anna Gabrielyan & Mary Hall & Simon A. Cobbold & Stephen Mieruszynski & Martin Brzozowski & Daniel S. Simpson & Hao Dong & , 2022. "Development of NanoLuc-targeting protein degraders and a universal reporter system to benchmark tag-targeted degradation platforms," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. 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.
    3. 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.
    4. 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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