美国范安德尔研究所Wei Lü和美国约翰霍普金斯大学医学院Zhaozhu Qiu研究组合作取得最新进展。他们揭示了质子激活的氯离子通道（PAC）的结构和pH敏感机制。2020年11月4日，《自然》杂志发表了这一成果。
他们介绍了人类PAC在高pH静息状态和低pH质子结合的非导电状态下的两种冷冻电镜结构。PAC是一个三聚体，其中每个亚基由一个跨膜结构域（TMD）和一个细胞外结构域（ECD）组成，该跨膜结构域由两个螺旋（TM1和TM2）形成。当pH从8降低到4时，他们观察到ECD-TMD界面和TMD的显著构象变化。
ECD-TMD界面的重排以组氨酸98残基的移动为特征，该残基在酸化后与静止位置脱钩，并插入约5Å的酸性袋中。在TMD内，TM1经历旋转运动，将其交互伙伴从其同源TM2切换到相邻的TM2。PAC的阴离子选择性由TM2上带正电荷的赖氨酸319残基决定，用谷氨酸残基取代赖氨酸319可将PAC转换为阳离子选择性通道。他们的数据提供了PAC分子组装的部分机制，并为理解质子依赖的激活机制提供了基础。
据悉，PAC在广泛的哺乳动物细胞中均具有活性，并参与酸诱导的细胞死亡和组织损伤。PAC最近被证明代表了一个新颖且进化上保守的蛋白质家族。
附：英文原文
Title: Structures and pH-sensing mechanism of the proton-activated chloride channel
Author: Zheng Ruan, James Osei-Owusu, Juan Du, Zhaozhu Qiu, Wei L
Issue&Volume: 2020-11-04
Abstract: The proton-activated chloride channel (PAC) is active across a wide range of mammalian cells and is involved in acid-induced cell death and tissue injury1,2,3. PAC has recently been shown to represent a novel and evolutionarily conserved protein family4,5. Here we present two cryo-electron microscopy structures of human PAC in a high-pH resting closed state and a low-pH proton-bound non-conducting state. PAC is a trimer in which each subunit consists of a transmembrane domain (TMD), which is formed of two helices (TM1 and TM2), and an extracellular domain (ECD). Upon a decrease of pH from 8 to 4, we observed marked conformational changes in the ECD–TMD interface and the TMD. The rearrangement of the ECD–TMD interface is characterized by the movement of the histidine 98 residue, which is, after acidification, decoupled from the resting position and inserted into an acidic pocket that is about 5 away. Within the TMD, TM1 undergoes a rotational movement, switching its interaction partner from its cognate TM2 to the adjacent TM2. The anion selectivity of PAC is determined by the positively charged lysine 319 residue on TM2, and replacing lysine 319 with a glutamate residue converts PAC to a cation-selective channel. Our data provide a glimpse of the molecular assembly of PAC, and a basis for understanding the mechanism of proton-dependent activation.
DOI: 10.1038/s41586-020-2875-7
Source: https://www.nature.com/articles/s41586-020-2875-7
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
