Conformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis

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; Phoebe P. C. Smith; Andrew I. Webb; Emma J. Petrie; Joanne M. Hildebrand; Natarajan Kannan; Peter E. Czabotar; Shohei Koide; James M. Murphy

doi:10.1038/s41467-021-22400-z

Nature Communications (Apr 2021)

Conformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis

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,
Phoebe P. C. Smith,
Andrew I. Webb,
Emma J. Petrie,
Joanne M. Hildebrand,
Natarajan Kannan,
Peter E. Czabotar,
Shohei Koide,
James M. Murphy

Affiliations

Sarah E. Garnish: Walter and Eliza Hall Institute of Medical Research
Yanxiang Meng: Walter and Eliza Hall Institute of Medical Research
Akiko Koide: Perlmutter Cancer Center, New York University Langone Health
Jarrod J. Sandow: Walter and Eliza Hall Institute of Medical Research
Eric Denbaum: Perlmutter Cancer Center, New York University Langone Health
Annette V. Jacobsen: Walter and Eliza Hall Institute of Medical Research
Wayland Yeung: Institute of Bioinformatics, University of Georgia
Andre L. Samson: Walter and Eliza Hall Institute of Medical Research
Christopher R. Horne: 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
Phoebe P. C. Smith: Walter and Eliza Hall Institute of Medical Research
Andrew I. Webb: Walter and Eliza Hall Institute of Medical Research
Emma J. Petrie: Walter and Eliza Hall Institute of Medical Research
Joanne M. Hildebrand: Walter and Eliza Hall Institute of Medical Research
Natarajan Kannan: Institute of Bioinformatics, University of Georgia
Peter E. Czabotar: Walter and Eliza Hall Institute of Medical Research
Shohei Koide: Perlmutter Cancer Center, New York University Langone Health
James M. Murphy: Walter and Eliza Hall Institute of Medical Research

DOI: https://doi.org/10.1038/s41467-021-22400-z
Journal volume & issue: Vol. 12, no. 1
pp. 1 – 14

Abstract

Read online

Mixed Lineage Kinase Domain-Like (MLKL) pseudokinase is phosphorylated by RIPK3 kinase prior to cell death by necroptosis. Here, the authors use monobodies that bind to the MLKL pseudokinase domain as tools, which allowed them to determine the crystal structures of the MLKL pseudokinase domain in two distinct conformations. By combining their structural data with cell signalling assays and MD simulations they provide evidence that endogenous MLKL preassociates with its upstream regulator RIPK3, and that MLKL disengages from RIPK3 following the induction of necroptosis.

Published in Nature Communications

ISSN: 2041-1723 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science
Website: https://www.nature.com/ncomms/

About the journal