Journal article
The brace helices of MLKL mediate interdomain communication and oligomerisation to regulate cell death by necroptosis
KA Davies, MC Tanzer, MDW Griffin, YF Mok, SN Young, R Qin, EJ Petrie, PE Czabotar, J Silke, JM Murphy
Cell Death and Differentiation | NATURE PUBLISHING GROUP | Published : 2018
Abstract
The programmed cell death pathway, necroptosis, relies on the pseudokinase, Mixed Lineage Kinase domain-Like (MLKL), for cellular execution downstream of death receptor or Toll-like receptor ligation. Receptor-interacting protein kinase-3 (RIPK3)-mediated phosphorylation of MLKL’s pseudokinase domain leads to MLKL switching from an inert to activated state, where exposure of the N-terminal four-helix bundle (4HB) ‘executioner’ domain leads to cell death. The precise molecular details of MLKL activation, including the stoichiometry of oligomer assemblies, mechanisms of membrane translocation and permeabilisation, remain a matter of debate. Here, we dissect the function of the two ‘brace’ heli..
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Awarded by Australian Research Council
Funding Acknowledgements
We thank staff at the Australian Synchrotron SAXS/WAXS beamline for assistance with data collection. We acknowledge support from an AINSE Postgraduate Research Award and an Australian Government Research Training Program Scholarship for KAD; a Victorian International Research Scholarship to MCT; RQ was supported by a scholarship from the Walter and Eliza Hall Institute as part of the International Student Program in Research Experience. We are grateful to the National Health and Medical Research Council for fellowship (PEC, 1079700; JS, 1058190; JMM, 1105754), grant (1057905; 1124735) and infrastructure (IRIISS 9000433) support; the Australian Research Council (Future Fellowship to MDWG, FT140100544); and to the Victorian Government Operational Infrastructure Support scheme.