The structural basis of the pH-homeostasis mediated by the Cl−/HCO3− exchanger, AE2
Qing Zhang, Liyan Jian, Deqiang Yao, Bing Rao, Ying Xia, Kexin Hu, Shaobai Li, Yafeng Shen, Cao Mi, An Qin, Jie Zhao, Yu Cao
Abstract
Abstract The cell maintains its intracellular pH in a narrow physiological range and disrupting the pH-homeostasis could cause dysfunctional metabolic states. Anion exchanger 2 (AE2) works at high cellular pH to catalyze the exchange between the intracellular HCO 3 − and extracellular Cl − , thereby maintaining the pH-homeostasis. Here, we determine the cryo-EM structures of human AE2 in five major operating states and one transitional hybrid state. Among those states, the AE2 shows the inward-facing, outward-facing, and intermediate conformations, as well as the substrate-binding pockets at two sides of the cell membrane. Furthermore, critical structural features were identified showing an interlock mechanism for interactions among the cytoplasmic N-terminal domain and the transmembrane domain and the self-inhibitory effect of the C-terminal loop. The structural and cell-based functional assay collectively demonstrate the dynamic process of the anion exchange across membranes and provide the structural basis for the pH-sensitive pH-rebalancing activity of AE2.