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Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization

Author

Listed:
  • Yanxiang Meng

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

  • Sarah E. Garnish

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

  • Katherine A. Davies

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

  • Katrina A. Black

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

  • Andrew P. Leis

    (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)

  • Joanne M. Hildebrand

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

  • Hanadi Hoblos

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

  • Cheree Fitzgibbon

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

  • Samuel N. Young

    (Walter and Eliza Hall Institute of Medical Research)

  • Toby Dite

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

  • Laura F. Dagley

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

  • Aarya Venkat

    (University of Georgia)

  • Natarajan Kannan

    (University of Georgia
    University of Georgia)

  • Akiko Koide

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

  • Shohei Koide

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

  • Alisa Glukhova

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

  • Peter E. Czabotar

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

  • James M. Murphy

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

Abstract

The necroptosis pathway is a lytic, pro-inflammatory mode of cell death that is widely implicated in human disease, including renal, pulmonary, gut and skin inflammatory pathologies. The precise mechanism of the terminal steps in the pathway, where the RIPK3 kinase phosphorylates and triggers a conformation change and oligomerization of the terminal pathway effector, MLKL, are only emerging. Here, we structurally identify RIPK3-mediated phosphorylation of the human MLKL activation loop as a cue for MLKL pseudokinase domain dimerization. MLKL pseudokinase domain dimerization subsequently drives formation of elongated homotetramers. Negative stain electron microscopy and modelling support nucleation of the MLKL tetramer assembly by a central coiled coil formed by the extended, ~80 Å brace helix that connects the pseudokinase and executioner four-helix bundle domains. Mutational data assert MLKL tetramerization as an essential prerequisite step to enable the release and reorganization of four-helix bundle domains for membrane permeabilization and cell death.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42255-w
    DOI: 10.1038/s41467-023-42255-w
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    as
    1. Katherine A. Davies & Cheree Fitzgibbon & Samuel N. Young & Sarah E. Garnish & Wayland Yeung & Diane Coursier & Richard W. Birkinshaw & Jarrod J. Sandow & Wil I. L. Lehmann & Lung-Yu Liang & Isabelle , 2020. "Distinct pseudokinase domain conformations underlie divergent activation mechanisms among vertebrate MLKL orthologues," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    2. 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.
    3. Juan Lin & Snehlata Kumari & Chun Kim & Trieu-My Van & Laurens Wachsmuth & Apostolos Polykratis & Manolis Pasparakis, 2016. "RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation," Nature, Nature, vol. 540(7631), pages 124-128, December.
    4. 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.
    5. 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.
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    7. 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.
    8. Andre L. Samson & Ying Zhang & Niall D. Geoghegan & Xavier J. Gavin & Katherine A. Davies & Michael J. Mlodzianoski & Lachlan W. Whitehead & Daniel Frank & Sarah E. Garnish & Cheree Fitzgibbon & Anne , 2020. "MLKL trafficking and accumulation at the plasma membrane control the kinetics and threshold for necroptosis," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    9. Kim Newton & Katherine E. Wickliffe & Allie Maltzman & Debra L. Dugger & Andreas Strasser & Victoria C. Pham & Jennie R. Lill & Merone Roose-Girma & Søren Warming & Margaret Solon & Hai Ngu & Joshua D, 2016. "RIPK1 inhibits ZBP1-driven necroptosis during development," Nature, Nature, vol. 540(7631), pages 129-133, December.
    10. Joanne M. Hildebrand & Maria Kauppi & Ian J. Majewski & Zikou Liu & Allison J. Cox & Sanae Miyake & Emma J. Petrie & Michael A. Silk & Zhixiu Li & Maria C. Tanzer & Gabriela Brumatti & Samuel N. Young, 2020. "A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
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