MLKL forms cation channels.
MLKL forms cation channels.
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MLKL 形成阳离子通道
DOI：
10.1038/cr.2016.26
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发表时间：
2016-05
期刊：
影响因子：
44.1
通讯作者：
Gao Z
中科院分区：
文献类型：
--
作者：
Xia B;Fang S;Chen X;Hu H;Chen P;Wang H;Gao Z
混合谱系激酶结构域样（MLKL）蛋白是肿瘤坏死因子诱导的坏死性凋亡的关键因素。最近关于坏死性凋亡执行的研究揭示了 MLKL 在膜破坏中的承诺作用。然而，我们对 MLKL 如何在膜上发挥作用的了解仍然非常有限。在这里，我们证明，在 Na+ 和 K+ 存在的情况下，MLKL 形成的阳离子通道优先渗透 Mg 2+ 而不是 Ca 2+。此外，含有六个螺旋（H1-H6）的N端结构域足以形成通道。利用取代半胱氨酸可达性方法，我们进一步确定螺旋H1、H2、H3、H5和H6是跨膜片段，而H4位于细胞质中。最后，MLKL 诱导的膜去极化和细胞死亡与其通道活性呈正相关。 Mg 2+ 优先渗透性和五跨膜段拓扑结构将 MLKL 与先前识别的 Mg 2+ 渗透性通道区分开来，从而将 MLKL 确立为一类新型阳离子通道。
The mixed lineage kinase domain-like (MLKL) protein is a key factor in tumor necrosis factor-induced necroptosis. Recent studies on necroptosis execution revealed a commitment role of MLKL in membrane disruption. However, our knowledge of how MLKL functions on membrane remains very limited. Here we demonstrate that MLKL forms cation channels that are permeable preferentially to Mg 2+ rather than Ca 2+ in the presence of Na+ and K+. Moreover, the N-terminal domain containing six helices (H1-H6) is sufficient to form channels. Using the substituted cysteine accessibility method, we further determine that helix H1, H2, H3, H5 and H6 are transmembrane segments, while H4 is located in the cytoplasm. Finally, MLKL-induced membrane depolarization and cell death exhibit a positive correlation to its channel activity. The Mg 2+-preferred permeability and five transmembrane segment topology distinguish MLKL from previously identified Mg 2+-permeable channels and thus establish MLKL as a novel class of cation channels.