MLKL forms cation channels

• Published in: Cell research Vol. 26; no. 5; pp. 517 - 528
• Main Authors: Xia, Bingqing, Fang, Sui, Chen, Xueqin, Hu, Hong, Chen, Peiyuan, Wang, Huayi, Gao, Zhaobing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2016; Nature Publishing Group
• Subjects: 631/45/269; 631/45/607/275; 631/80/82/2344; Biomedical and Life Sciences; Ca2; Cations; Cell Biology; Cell Death; HEK293 Cells; Humans; Ion Channel Gating; Ion Channels - chemistry; Ion Channels - metabolism; Life Sciences; Lipid Bilayers - metabolism; Magnesium - metabolism; N-末端; Original; original-article; Protein Kinases - chemistry; Protein Kinases - metabolism; Protein Structure, Secondary; SIS; Topology; 离子通道; 细胞死亡; 肿瘤坏死因子; 膜破裂; cation channel; bilayer lipid membrane; MLKL; magnesium channel; necroptosis
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/cr.2016.26

The mixed lineage kinase domain-like （MLKL） protein is a key factor in tumor necrosis factor-induced necropto- sis. 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 Mg2＋ rather than Caz＋ in the presence of Na＋ and K＋. Moreover, the N-terminal domain containing six helices （HI-H6） is sufficient to form channels. Using the substituted eysteine accessibility method, we further determine that helix HI, 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 2＋ Mg -preferred permeability and five transmembrane segment topology distin- guish MLKL from previously identified Mg2＋-permeable channels and thus establish MLKL as a novel class of cation channels.