State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Bioactive Small Molecules, Collaborative Innovation Center of Genetics and Development, Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai 200438, China.
Department of Basic Medicine, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 200098, China.
Proc Natl Acad Sci U S A. 2024 Oct 29;121(44):e2405659121. doi: 10.1073/pnas.2405659121. Epub 2024 Oct 23.
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 Zn-activated ion channel that is widely expressed in the human body and is conserved among eukaryotes. Due to its gating by extracellular Zn, ZAC has been considered a Zn 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 Zn 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.
Cys 环受体是一个包含多种生理功能的五聚体配体门控离子通道超家族，特别是在中枢神经系统的神经递质传递中。其中，锌激活通道（ZAC）是一种在人体中广泛表达且在真核生物中保守的 Zn 激活离子通道。由于其通过细胞外 Zn 门控，ZAC 被认为是一种 Zn 传感器，但自分子克隆以来，其结构和功能特征的研究很少。在 Cys 环受体超家族的各个家族中，只有 ZAC 的结构尚未被确定。在这里，我们确定了 apo 状态下 ZAC 的冷冻电镜结构，并进行了基于结构的突变分析。我们鉴定了细胞外结构域中的几个残基，其突变对 Zn 敏感性有轻微影响。离子传导通道中的紧缩位点与其他 Cys 环受体结构不同，进一步的突变分析确定了一个对离子选择性很重要的关键残基。总之，我们的工作为理解 ZAC 的离子传导机制提供了一个结构框架。
