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

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 Dite, Laura F. Dagley, Aarya Venkat, Natarajan Kannan, Akiko Koide, Shohei Koide, Alisa Glukhova, Peter E. Czabotar () and James M. Murphy ()
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Yanxiang Meng: Walter and Eliza Hall Institute of Medical Research
Sarah E. Garnish: Walter and Eliza Hall Institute of Medical Research
Katherine A. Davies: Walter and Eliza Hall Institute of Medical Research
Katrina A. Black: Walter and Eliza Hall Institute of Medical Research
Andrew P. Leis: Walter and Eliza Hall Institute of Medical Research
Christopher R. Horne: Walter and Eliza Hall Institute of Medical Research
Joanne M. Hildebrand: Walter and Eliza Hall Institute of Medical Research
Hanadi Hoblos: Walter and Eliza Hall Institute of Medical Research
Cheree Fitzgibbon: Walter and Eliza Hall Institute of Medical Research
Samuel N. Young: Walter and Eliza Hall Institute of Medical Research
Toby Dite: Walter and Eliza Hall Institute of Medical Research
Laura F. Dagley: Walter and Eliza Hall Institute of Medical Research
Aarya Venkat: University of Georgia
Natarajan Kannan: University of Georgia
Akiko Koide: New York University Langone Health
Shohei Koide: New York University Langone Health
Alisa Glukhova: Walter and Eliza Hall Institute of Medical Research
Peter E. Czabotar: Walter and Eliza Hall Institute of Medical Research
James M. Murphy: Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42255-w

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