Cryo- EM structure of the zinc- activated channel (ZAC) in the Cys- loop receptor superfamily

• 成果类型: Article
• 署名作者: Jin, Fei; Lin, Yi-Yu; Wang, Ru-Chun; Xie, Tang-Xuan; Zhao, Yimeng; Shen, Cheng; Sheng, Danqi; Ichikawa, Muneyoshi; Yu, Ye; Wang, Jin; Hattori, Motoyuki
• 署名单位: Fudan University; China Pharmaceutical University; Fudan University; Fudan University; China Pharmaceutical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15337
• DOI: 10.1073/pnas.2405659121
• 发表日期: 2024-10-29
• 关键词: gated ion-channel; nicotinic acetylcholine-receptor; x-ray-structure; charge selectivity; gating mechanism; desensitization; expression; alpha-7; proteins; features

摘要

Cys-loop receptors are a large superfamily of pentameric ligand-gated ion channels with various physiological roles, especially in neurotransmission in the central nervous system. Among them, zinc- activated channel (ZAC) is a Zn2+- activated ion channel that is widely expressed in the human body and is conserved amongeukaryotes. Due to its gating by extracellular Zn2+, ZAC has been considered a Zn2+ sensor, but it has undergone minimal structural and functional characterization since its molecular cloning. Among the families in the Cys-loop receptor superfamily, only the structure of ZAC has yet to be determined. Here, we determined the cryo-EM structure of ZAC in the apo state and performed structure- based mutation analyses. We identified a few residues in the extracellular domain whose mutations had a mild impact on Zn2+ sensitivity. The constriction site in the ion- conducting pore differs from the one in other Cys-loop receptor structures, and further mutational analysis identified a key residue that is important for ion selectivity. In summary, our work provides a structural framework for understanding the ion- conducting mechanism of ZAC.