Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization.
Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization.
复制标题
磷酸化依赖的假激酶结构域二聚化驱动全长MLKL寡聚化。
DOI：
10.1038/s41467-023-42255-w
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发表时间：
2023-10-26
影响因子：
16.6
通讯作者：
Murphy, James M.
中科院分区：
文献类型：
--
作者：
Meng, Yanxiang;Garnish, Sarah E.;Davies, Katherine A.;Black, Katrina A.;Leis, Andrew P.;Horne, Christopher R.;Hildebrand, Joanne M.;Hoblos, Hanadi;Fitzgibbon, Cheree;Young, Samuel N.;Dite, Toby;Dagley, Laura F.;Venkat, Aarya;Kannan, Natarajan;Koide, Akiko;Koide, Shohei;Glukhova, Alisa;Czabotar, Peter E.;Murphy, James M.
坏死下垂途径是细胞死亡的一种溶解性、促炎模式，广泛涉及人类疾病，包括肾脏、肺、肠道和皮肤炎症病理。该通路末端步骤的确切机制，即RIPK3激酶磷酸化并触发末端通路效应物MLKL的构象变化和寡聚化，目前才刚刚出现。在这里，我们从结构上确定了ripk3介导的人MLKL激活环磷酸化作为MLKL假激酶结构域二聚化的线索。MLKL伪激酶结构域二聚化随后驱动长形同源四聚体的形成。负染色电镜和建模支持MLKL四聚体组装成核的中心线圈形成的延伸，~80 Å支撑螺旋，连接伪激酶和刽子手四螺旋束域。突变数据表明，MLKL四聚化是使四螺旋束结构域释放和重组以实现膜渗透和细胞死亡的必要先决条件。坏死的刽子手MLKL是如何转变成杀手的一直是个谜。在这里，作者表明ripk3介导的人MLKL磷酸化是在促坏死MLKL四聚体组装之前假激酶结构域二聚化的线索。
The necroptosis pathway is a lytic, pro-inflammatory mode of cell death that is widely implicated in human disease, including renal, pulmonary, gut and skin inflammatory pathologies. The precise mechanism of the terminal steps in the pathway, where the RIPK3 kinase phosphorylates and triggers a conformation change and oligomerization of the terminal pathway effector, MLKL, are only emerging. Here, we structurally identify RIPK3-mediated phosphorylation of the human MLKL activation loop as a cue for MLKL pseudokinase domain dimerization. MLKL pseudokinase domain dimerization subsequently drives formation of elongated homotetramers. Negative stain electron microscopy and modelling support nucleation of the MLKL tetramer assembly by a central coiled coil formed by the extended, ~80 Å brace helix that connects the pseudokinase and executioner four-helix bundle domains. Mutational data assert MLKL tetramerization as an essential prerequisite step to enable the release and reorganization of four-helix bundle domains for membrane permeabilization and cell death. How the necroptosis executioner, MLKL, converts to a killer form has been mysterious. Here, authors show RIPK3-mediated phosphorylation of human MLKL is the cue for pseudokinase domain dimerization before assembly of pro-necroptotic MLKL tetramers.
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影响因子：
12.4
作者：
Bader, Stefanie M.;Preston, Simon P.;Saliba, Katie;Lipszyc, Adam;Grant, Zoe L.;Mackiewicz, Liana;Baldi, Andrew;Hempel, Anne;Clark, Michelle P.;Peiris, Thanushi;Clow, William;Bjelic, Jan;Stutz, Michael D.;Arandjelovic, Philip;Teale, Jack;Du, Fashuo;Coultas, Leigh;Murphy, James M.;Allison, Cody C.;Pellegrini, Marc;Samson, Andre L.
通讯作者：
Samson, Andre L.
影响因子：
16.6
作者：
Davies, Katherine A.;Fitzgibbon, Cheree;Murphy, James M.
通讯作者：
Murphy, James M.
影响因子：
12.4
作者：
Davies, Katherine A.;Tanzer, Maria C.;Murphy, James M.
通讯作者：
Murphy, James M.
影响因子：
8.8
作者：
Dondelinger, Yves;Declercq, Wim;Vandenabeele, Peter
通讯作者：
Vandenabeele, Peter
DOI：
10.1107/s0907444910026582
发表时间：
2010-11-01
影响因子：
2.2
作者：
Afonine, Pavel V.;Mustyakimov, Marat;Adams, Paul D.
通讯作者：
Adams, Paul D.