Structure and mechanism of NALCN-FAM155A-UNC79-UNC80 channel complex
Open accessPublished version of a preprint
Abstract
NALCN channel mediates sodium leak currents and is important for maintaining proper resting membrane potential. NALCN and FAM155A form the core complex of the channel, the activity of which essentially depends on the presence of both UNC79 and UNC80, two auxiliary proteins. NALCN, FAM155A, UNC79, and UNC80 co-assemble into a large hetero-tetrameric channel complex. Genetic mutations of NALCN channel components lead to neurodevelopmental diseases. However, the structure and mechanism of the intact channel complex remain elusive. Here, we present the cryo-EM structure of the mammalian NALCN-FAM155A-UNC79-UNC80 quaternary complex. The structure shows that UNC79-UNC80 form a large piler-shaped heterodimer which was tethered to the intracellular side of the NALCN channel through tripartite interactions with the cytoplasmic loops of NALCN. Two interactions are essential for proper cell surface localization of NALCN. The other interaction relieves the self-inhibition of NALCN by pulling the auto-inhibitory CTD Interacting Helix (CIH) out of its binding site. Our work defines the structural mechanism of NALCN modulation by UNC79 and UNC80.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Structure of a Pancreatic ATP-Sensitive Potassium Channel
Li, N., Wu, J.-X., Ding, D., Cheng, J., Gao, N., & Chen, L. (2017) · Cell · doi:10.1016/j.cell.2016.12.028 · Cited by 252 · see citing works
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- Authors
- Kang, Y., & Chen, L.
- Affiliations
- Peking University (CN)
- Corresponding author
- Chen, Lei
- ORCID
- Venue
- Nature Communications
- Published
- 2022-05-12
- Volume
- 13
- Issue
- 1
- Pages
- 2639-2639
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9098444
- OpenAlex
- W4280534525
- Cited by
- 31
- References
- 2
- Citations by year
- 2026: 2 · 2025: 12 · 2024: 7 · 2023: 9 · 2022: 1
- FWCI
- 2.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (91957201, 31870833, and 31821091)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- cryo-EM structure, heterotetrameric channels, cell surface localization, neurodevelopmental disorders, resting membrane potential
- MeSH terms
- Protein Domains, Animals, Ion Channels, Mammals, Membrane Potentials, Membrane Proteins, Mutation
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