Journal article

Membrane permeabilization is mediated by distinct epitopes in mouse and human orthologs of the necroptosis effector, MLKL

Ashish Sethi, Christopher Horne, Cheree Fitzgibbon, Karyn Wilde, Katherine Davies, Sarah Garnish, Annette Jacobsen, André Samson, Joanne Hildebrand, Ahmad Wardak, Peter Czabotar, Emma Petrie, Paul Gooley, James Murphy

Cold Spring Harbor Laboratory | Published : 2021

Abstract

ABSTRACT Necroptosis is a lytic programmed cell death pathway with origins in innate immunity that is frequently dysregulated in inflammatory diseases. The terminal effector of the pathway, MLKL, is licensed to kill following phosphorylation of its pseudokinase domain by the upstream regulator, RIPK3 kinase. Phosphorylation provokes the unleashing of MLKL’s N-terminal four-helix bundle (4HB or HeLo) domain, which binds and permeabilizes the plasma membrane to cause cell death. The precise mechanism by which the 4HB domain permeabilizes membranes, and how the mechanism differs between species, remains unclear. Here, we identify the membrane binding epitope of mouse MLKL using NMR spectroscopy..

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