期刊
CELL RESEARCH
卷 26, 期 5, 页码 517-528出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cr.2016.26
关键词
MLKL; magnesium channel; bilayer lipid membrane; cation channel; necroptosis
类别
资金
- State Key Program of Basic Research of China [2013CB910604]
- National Natural Science Foundation of China [61327014, 61175103, 61433017, 31571427]
- External Cooperation Program of BIC, Chinese Academy of Sciences [1536631KYSB20130003]
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 Mg2+ rather than Ca2+ 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 Mg2+-preferred permeability and five transmembrane segment topology distinguish MLKL from previously identified Mg2+-permeable channels and thus establish MLKL as a novel class of cation channels.
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