Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis.
Conformational switching of the pseudokinase domain promotes human MLKL tetramerization and cell death by necroptosis.
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DOI：
10.1038/s41467-018-04714-7
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发表时间：
2018-06-21
影响因子：
16.6
通讯作者：
Murphy JM
中科院分区：
文献类型：
--
作者：
Petrie EJ;Sandow JJ;Jacobsen AV;Smith BJ;Griffin MDW;Lucet IS;Dai W;Young SN;Tanzer MC;Wardak A;Liang LY;Cowan AD;Hildebrand JM;Kersten WJA;Lessene G;Silke J;Czabotar PE;Webb AI;Murphy JM
坏死性细胞死亡由该途径的最末端已知效应物MLKL介导。上游激酶RIPK 3对MLKL假激酶结构域激活环的磷酸化如何诱导MLKL的N-末端执行者四螺旋束（4 HB）结构域的解蔽、高阶组装和质膜的透化仍然知之甚少。在这里，我们揭示了存在的基础单体MLKL构象存在于人体细胞暴露于坏死性凋亡刺激之前。活化后，MLKL假激酶结构域内的切换促进4 HB结构域从假激酶结构域αC螺旋和假催化环脱离，从而形成坏死性凋亡诱导四聚体。与小鼠MLKL相反，人MLKL假激酶结构域中RIPK 3底物位点的取代完全消除了坏死性凋亡信号传导。因此，虽然小鼠和人MLKL的假激酶结构域作为分子开关来控制MLKL活化，但物种之间的潜在机制不同。RIPK 3介导的混合谱系激酶结构域样（MLKL）假激酶的磷酸化被认为是坏死性凋亡信号传导期间MLKL活化的触发因素。在此，作者提供了人MLKL从单体状态到四聚体的转变对于坏死性凋亡信号传导至关重要的证据。
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. Therefore, while the pseudokinase domains of mouse and human MLKL function as molecular switches to control MLKL activation, the underlying mechanism differs between species. RIPK3-mediated phosphorylation of the mixed lineage kinase domain-like (MLKL) pseudokinase is thought to be the trigger for MLKL activation during necroptotic signaling. Here the authors provide evidence that the transition of human MLKL from a monomeric state to a tetramer is essential for necroptosis signalling.
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影响因子：
8.8
作者：
Dondelinger, Yves;Declercq, Wim;Vandenabeele, Peter
通讯作者：
Vandenabeele, Peter
影响因子：
6.1
作者：
Konarev, PV;Volkov, VV;Svergun, DI
通讯作者：
Svergun, DI
影响因子：
12.4
作者：
Davies, Katherine A.;Tanzer, Maria C.;Murphy, James M.
通讯作者：
Murphy, James M.
DOI：
10.1073/pnas.1320298111
发表时间：
2014-07-01
影响因子：
11.1
作者：
Leitner, Alexander;Joachimiak, Lukasz A.;Aebersold, Ruedi
通讯作者：
Aebersold, Ruedi
影响因子：
12.4
作者：
Cook, W. D.;Moujalled, D. M.;Vaux, D. L.
通讯作者：
Vaux, D. L.