The structural basis of the pH-homeostasis mediated by the Cl−/HCO3− exchanger, AE2

• Published in: Nature communications 2023-03, Vol.14 (1), p.1812-1812, Article 1812
• Main Authors: Zhang, Qing, Jian, Liyan, Yao, Deqiang, Rao, Bing, Xia, Ying, Hu, Kexin, Li, Shaobai, Shen, Yafeng, Cao, Mi, Qin, An, Zhao, Jie, Cao, Yu
• Format: Article
• Language: English
• Subjects: 101/28; 631/45/612/1237; 631/535/1258/1259; 631/57/2283; 82/16; 82/29; 82/80; 82/83; Anion exchange; Anion exchanging; Bicarbonates; Cell membranes; Domains; Homeostasis; Humanities and Social Sciences; Intracellular; multidisciplinary; pH effects; Physiology; Science; Science (multidisciplinary); Structure-function relationships; Substrates
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37557-y

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. Cells maintain a narrow physiological pH by exchanging intracellular bicarbonate for extracellular chloride. Here, authors determine the cryo-EM structures of human anion exchanger 2 (AE2) in five major operating states and one transitional state, to collectively demonstrate the process of pH-balancing.