Sequential Engagement of Distinct MLKL Phosphatidylinositol-Binding Sites Executes Necroptosis.
Sequential Engagement of Distinct MLKL Phosphatidylinositol-Binding Sites Executes Necroptosis.
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DOI：
10.1016/j.molcel.2016.01.011
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发表时间：
2016-02-18
期刊：
影响因子：
16
通讯作者：
Green DR
中科院分区：
文献类型：
--
作者：
Quarato G;Guy CS;Grace CR;Llambi F;Nourse A;Rodriguez DA;Wakefield R;Frase S;Moldoveanu T;Green DR
坏死性下垂是一种受受体相互作用蛋白激酶3(RIPK3)和混合谱系蛋白激酶结构域样(MLKL)假激酶调控的细胞死亡途径。MLKL在被RIPK3磷酸化后如何执行质膜破裂仍存在争议。在这里，我们描述了MLKL结构变化的分级转导，最终导致坏死性下垂。MLKL支架位于N-末端螺旋束(NB)的近端，参与齐聚反应，通过NB与磷脂酰肌醇(PIP)磷脂的磷酸化肌醇极性基团的低亲和力结合来促进质膜靶向。在膜上，NB经历了“翻滚”机制，以暴露额外的高亲和力PIP结合位点，负责与膜的牢固结合和支架从NB的位移。PI(4，5)P2是首选的PIP结合伙伴。我们研究了MLKL与PIP的特异性关联以及在坏死性下垂过程中随后的结构变化。
Necroptosis is a cell death pathway regulated by the receptor interacting protein kinase 3 (RIPK3) and the mixed lineage kinase domain-like (MLKL) pseudokinase. How MLKL executes plasma membrane rupture upon phosphorylation by RIPK3 remains controversial. Here, we characterize the hierarchical transduction of structural changes in MLKL that culminate in necroptosis. The MLKL brace, proximal to the N-terminal helix bundle (NB), is involved in oligomerization to facilitate plasma membrane targeting through the low-affinity binding of NB to phosphorylated inositol polar head groups of phosphatidylinositol phosphate (PIP) phospholipids. At the membrane, the NB undergoes a “rolling over” mechanism to expose additional higher-affinity PIP-binding sites responsible for robust association to the membrane and displacement of the brace from the NB. PI(4,5)P2 is the preferred PIP-binding partner. We investigate the specific association of MLKL with PIPs and subsequent structural changes during necroptosis.