MLKL forms cation channels
Open accessAbstract
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.
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Once localized at plasma membrane, MLKL activates cell-surface proteases of ADAM family, which can promote shedding of plasma membrane-associated proteins, or form Mg2+ permeant channels.
“Once localized at the plasma membrane, MLKL reportedly activates cell-surface proteases of the ADAM family, which can promote the shedding of plasma membrane-associated proteins [458], or form Mg2+ permeant channels [459].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [459]
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- Authors
- Xia, B., Fang, S., Chen, X., Hu, H., Chen, P., Wang, H., & Gao, Z.
- Affiliations
- Chinese Academy of Sciences (CN)
- ShanghaiTech University (CN)
- Corresponding author
- Wang, Huayi
- Gao, Zhaobing
- Venue
- Cell Research
- Published
- 2016-04-01
- Volume
- 26
- Issue
- 5
- Pages
- 517-528
- ISSN
- 1001-0602 (ISSN-L)
- 1748-7838
- PMC
- PMC4856759
- OpenAlex
- W2329801438
- Cited by
- 202
- References
- 49
- Citations by year
- 2026: 10 · 2025: 26 · 2024: 16 · 2023: 26 · 2022: 16 · 2021: 24 · 2020: 25 · 2019: 23 · 2018: 16 · 2017: 11 · 2016: 8
- FWCI
- 10.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Research (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (61433017, 31571427, 61175103, 61327014)
- Chinese Academy of Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Physiology › Erythrocyte Function and Pathophysiology
- Keywords
- MLKL, cation channels, necroptosis, TNF-α, membrane permeabilization, transmembrane helices, membrane depolarization, cell death, N-terminal domain
- MeSH terms
- Cations, Humans, Ion Channels, Lipid Bilayers, Magnesium, Protein Kinases, Ion Channel Gating, Cell Death, Protein Structure, Secondary, HEK293 Cells
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