IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v11y2020i1d10.1038_s41467-020-16823-3.html
   My bibliography  Save this article

Distinct pseudokinase domain conformations underlie divergent activation mechanisms among vertebrate MLKL orthologues

Author

Listed:
  • Katherine A. Davies

    (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)

  • Sarah E. Garnish

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

  • Wayland Yeung

    (University of Georgia)

  • Diane Coursier

    (Walter and Eliza Hall Institute of Medical Research)

  • Richard W. Birkinshaw

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

  • Jarrod J. Sandow

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

  • Wil I. L. Lehmann

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

  • Lung-Yu Liang

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

  • Isabelle S. Lucet

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

  • James D. Chalmers

    (University of Otago)

  • Wayne M. Patrick

    (Victoria University of Wellington)

  • Natarajan Kannan

    (University of Georgia)

  • Emma J. Petrie

    (Walter and Eliza Hall Institute of Medical Research
    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)

Abstract

The MLKL pseudokinase is the terminal effector in the necroptosis cell death pathway. Phosphorylation by its upstream regulator, RIPK3, triggers MLKL’s conversion from a dormant cytoplasmic protein into oligomers that translocate to, and permeabilize, the plasma membrane to kill cells. The precise mechanisms underlying these processes are incompletely understood, and were proposed to differ between mouse and human cells. Here, we examine the divergence of activation mechanisms among nine vertebrate MLKL orthologues, revealing remarkable specificity of mouse and human RIPK3 for MLKL orthologues. Pig MLKL can restore necroptotic signaling in human cells; while horse and pig, but not rat, MLKL can reconstitute the mouse pathway. This selectivity can be rationalized from the distinct conformations observed in the crystal structures of horse and rat MLKL pseudokinase domains. These studies identify important differences in necroptotic signaling between species, and suggest that, more broadly, divergent regulatory mechanisms may exist among orthologous pseudoenzymes.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16823-3
    DOI: 10.1038/s41467-020-16823-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-020-16823-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-020-16823-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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. 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.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16823-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.