Journal article
The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism
JM Murphy, PE Czabotar, JM Hildebrand, IS Lucet, JG Zhang, S Alvarez-Diaz, R Lewis, N Lalaoui, D Metcalf, AI Webb, SN Young, LN Varghese, GM Tannahill, EC Hatchell, IJ Majewski, T Okamoto, RCJ Dobson, DJ Hilton, JJ Babon, NA Nicola Show all
Immunity | Published : 2013
Abstract
Mixed lineage kinase domain-like (MLKL) is a component of the "necrosome," the multiprotein complex that triggers tumor necrosis factor (TNF)-induced cell death by necroptosis. To define the specific role and molecular mechanism of MLKL action, we generated MLKL-deficient mice and solved the crystal structure of MLKL. Although MLKL-deficient mice were viable and displayed no hematopoietic anomalies or other obvious pathology, cells derived from these animals were resistant to TNF-induced necroptosis unless MLKL expression was restored. Structurally, MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase..
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Awarded by Cancer Council Victoria
Funding Acknowledgements
We thank staff in the WEHI Bioservices facility, V. Dixit for Ripk3<SUP>-/-</SUP> mice, J. Rickard for generating Ripk3<SUP>-/-</SUP> MDFs, P. Colman and D. Huang for discussions, MX and SAXS beamline staff at the Australian Synchrotron, the Monash University Protein Production Unit for access to the Corbett RT-PCR instrument, and J. Corbin, L. DiRago, C. Hyland, S. Mifsud, D. Stockwell, and T. Willson for technical assistance. This work was supported by NHMRC grants (1016647, 461221, 1016701, 637342, 1025594, 1046984) and fellowships to J. M. H., I. J. M., D. J. H., N.A.N., A. S., J. S., and W. S. A.; ARC fellowships to J. M. M., P. E. C., T.O., and J. J. B.; a Cancer Council Victoria fellowship to D. M.; Leukaemia Foundation and Australian Stem Cell Centre scholarships to L.N.V.; and additional support from the Australian Cancer Research Fund, Victorian State Government Operational Infrastructure Support, and NHMRC IRIISS grant (361646).