作者
Emma J Petrie, Jarrod J Sandow, Annette V Jacobsen, Brian J Smith, Michael DW Griffin, Isabelle S Lucet, Weiwen Dai, Samuel N Young, Maria C Tanzer, Ahmad Wardak, Lung-Yu Liang, Angus D Cowan, Joanne M Hildebrand, Wilhelmus JA Kersten, Guillaume Lessene, John Silke, Peter E Czabotar, Andrew I Webb, James M Murphy
发表日期
2018/6/21
期刊
Nature communications
卷号
9
期号
1
页码范围
2422
出版商
Nature Publishing Group UK
简介
Necroptotic 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 …
学术搜索中的文章
EJ Petrie, JJ Sandow, AV Jacobsen, BJ Smith… - Nature communications, 2018