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, Mi Cao, An Qin, Jie Zhao and Yu Cao ()
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Qing Zhang: Shanghai Jiao Tong University School of Medicine
Liyan Jian: Shanghai Jiao Tong University School of Medicine
Deqiang Yao: Shanghai Jiao Tong University School of Medicine
Bing Rao: Shanghai Jiao Tong University School of Medicine
Ying Xia: Shanghai Jiao Tong University School of Medicine
Kexin Hu: Shanghai Jiao Tong University School of Medicine
Shaobai Li: Shanghai Jiao Tong University School of Medicine
Yafeng Shen: Shanghai Jiao Tong University School of Medicine
Mi Cao: Shanghai Jiao Tong University School of Medicine
An Qin: Shanghai Jiao Tong University School of Medicine
Jie Zhao: Shanghai Jiao Tong University School of Medicine
Yu Cao: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-11

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 HCO3− 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.

Date: 2023
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DOI: 10.1038/s41467-023-37557-y

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