Journal
SCIENCE ADVANCES
Volume 7, Issue 9, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abe5983
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Funding
- NIH [R01NS099341, R01NS109307, R01AA027065, R01DK103901]
- Washington University Center for Cellular Imaging
- Washington University School of Medicine
- Children's Discovery Institute of Washington University
- St. Louis Children's Hospital [CDI-CORE-2015-505, CDI-CORE-2019-813]
- Foundation for Barnes-Jewish Hospital [3770]
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The study revealed the structure of TMEM206, a trimeric channel with a specific chloride ion selectivity filter, closely resembling the epithelial sodium channel/degenerin family of sodium channels in structure and assembly, although conducting chloride ions.
TMEM206 has been recently identified as an evolutionarily conserved chloride channel that underlies ubiquitously expressed, proton-activated, outwardly rectifying anion currents. Here, we report the cryo-electron microscopy structure of pufferfish TMEM206, which forms a trimeric channel, with each subunit comprising two transmembrane segments and a large extracellular domain. An ample vestibule in the extracellular region is accessible laterally from the three side portals. The central pore contains multiple constrictions. A conserved lysine residue near the cytoplasmic end of the inner helix forms the presumed chloride ion selectivity filter. Unprecedentedly, the core structure and assembly closely resemble those of the epithelial sodium channel/degenerin family of sodium channels that are unrelated in amino acid sequence and conduct cations instead of anions. Together with electrophysiology, this work provides insights into ion conduction and gating for a new class of chloride channels that is architecturally distinct from previously characterized chloride channel families.
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