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

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, Angus D. Cowan, Joanne M. Hildebrand, Wilhelmus J. A. Kersten, Guillaume Lessene, John Silke, Peter E. Czabotar, Andrew I. Webb and James M. Murphy ()
Additional contact information
Emma J. Petrie: The Walter & Eliza Hall Institute of Medical Research
Jarrod J. Sandow: The Walter & Eliza Hall Institute of Medical Research
Annette V. Jacobsen: The Walter & Eliza Hall Institute of Medical Research
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
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
Ahmad Wardak: The Walter & Eliza Hall Institute of Medical Research
Lung-Yu Liang: The Walter & Eliza Hall Institute of Medical Research
Angus D. Cowan: The Walter & Eliza Hall Institute of Medical Research
Joanne M. Hildebrand: The Walter & Eliza Hall Institute of Medical Research
Wilhelmus J. A. Kersten: The Walter & Eliza Hall Institute of Medical Research
Guillaume Lessene: The Walter & Eliza Hall Institute of Medical Research
John Silke: The Walter & Eliza Hall Institute of Medical Research
Peter E. Czabotar: The Walter & Eliza Hall Institute of Medical Research
Andrew I. Webb: The Walter & Eliza Hall Institute of Medical Research
James M. Murphy: The Walter & Eliza Hall Institute of Medical Research

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04714-7

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