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dc.contributor.authorPetrie, EJ
dc.contributor.authorSandowl, JJ
dc.contributor.authorJacobsen, A
dc.contributor.authorSmith, BJ
dc.contributor.authorGriffin, MDW
dc.contributor.authorLucet, IS
dc.contributor.authorDai, W
dc.contributor.authorYoung, SN
dc.contributor.authorTanzer, MC
dc.contributor.authorWardak, A
dc.contributor.authorLiang, L-Y
dc.contributor.authorCowan, AD
dc.contributor.authorHildebrand, JM
dc.contributor.authorKersten, WJA
dc.contributor.authorLessene, G
dc.contributor.authorSilke, J
dc.contributor.authorCzabotar, PE
dc.contributor.authorWebb, A
dc.contributor.authorMurphy, JM
dc.date.accessioned2020-12-17T04:34:46Z
dc.date.available2020-12-17T04:34:46Z
dc.date.issued2018-06-21
dc.identifierpii: 10.1038/s41467-018-04714-7
dc.identifier.citationPetrie, E. J., Sandowl, J. J., Jacobsen, A., Smith, B. J., Griffin, M. D. W., Lucet, I. S., Dai, W., Young, S. N., Tanzer, M. C., Wardak, A., Liang, L. -Y., Cowan, A. D., Hildebrand, J. M., Kersten, W. J. A., Lessene, G., Silke, J., Czabotar, P. E., Webb, A. & Murphy, J. M. (2018). Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis. NATURE COMMUNICATIONS, 9 (1), https://doi.org/10.1038/s41467-018-04714-7.
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/11343/255369
dc.description.abstractNecroptotic cell death is mediated by the most terminal known effector of the pathway, MLKL. Precisely how phosphorylation of the MLKL pseudokinase domain activation loop by the upstream kinase, RIPK3, induces unmasking of the N-terminal executioner four-helix bundle (4HB) domain of MLKL, higher-order assemblies, and permeabilization of plasma membranes remains poorly understood. Here, we reveal the existence of a basal monomeric MLKL conformer present in human cells prior to exposure to a necroptotic stimulus. Following activation, toggling within the MLKL pseudokinase domain promotes 4HB domain disengagement from the pseudokinase domain αC helix and pseudocatalytic loop, to enable formation of a necroptosis-inducing tetramer. In contrast to mouse MLKL, substitution of RIPK3 substrate sites in the human MLKL pseudokinase domain completely abrogated necroptotic signaling. Therefore, while the pseudokinase domains of mouse and human MLKL function as molecular switches to control MLKL activation, the underlying mechanism differs between species.
dc.languageEnglish
dc.publisherNATURE PUBLISHING GROUP
dc.titleConformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis
dc.typeJournal Article
dc.identifier.doi10.1038/s41467-018-04714-7
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.affiliation.departmentBiochemistry and Molecular Biology
melbourne.affiliation.department
melbourne.source.titleNature Communications
melbourne.source.volume9
melbourne.source.issue1
dc.rights.licenseCC BY
melbourne.elementsid1337043
melbourne.contributor.authorLessene, Guillaume
melbourne.contributor.authorJacobsen, Annette
melbourne.contributor.authorSilke, John
melbourne.contributor.authorMurphy, James
melbourne.contributor.authorGriffin, Michael
melbourne.contributor.authorPetrie, Emma
melbourne.contributor.authorSandow, Jarrod
melbourne.contributor.authorLucet, Isabelle
melbourne.contributor.authorHildebrand, Joanne
melbourne.contributor.authorKersten, Wilhelmus
melbourne.contributor.authorCzabotar, Peter
melbourne.contributor.authorWebb, Andrew
melbourne.contributor.authorTanzer, Maria
melbourne.contributor.authorCowan, Angus
dc.identifier.eissn2041-1723
melbourne.accessrightsOpen Access


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