Journal article
Membrane permeabilization is mediated by distinct epitopes in mouse and human orthologs of the necroptosis effector, MLKL
A Sethi, CR Horne, C Fitzgibbon, K Wilde, KA Davies, SE Garnish, AV Jacobsen, AL Samson, JM Hildebrand, A Wardak, PE Czabotar, EJ Petrie, PR Gooley, JM Murphy
Cell Death and Differentiation | Published : 2022
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. Using l..
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Awarded by University of Melbourne
Funding Acknowledgements
We are grateful to the NMR facility (University of Melbourne) and the National Deuteration Facility for providing crucial infrastructure for this study. The University of Melbourne NMR facility was enabled by an Australian Research Council equipment grant LE120100022. We are grateful to the National Health and Medical Research Council for fellowship (JMH, 1142669; PEC, 1079700; JMM, 1172929), grant (1124735, 2002965) and infrastructure (IRIISS 9000719) support; Anaxis Pharma Pty Ltd for funding support; and the Victorian Government Operational Infrastructure Support scheme. We acknowledge Australian Government Research Training Program Stipend Scholarship support (to SEG and AVJ) and the Wendy Dowsett Scholarship (to SEG). The National Deuteration Facility is partly funded by the National Collaborative Research Infrastructure Strategy (NCRIS), an Australian Government initiative.