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The structural basis of the pH-homeostasis mediated by the Cl(−)/HCO(3)(−) exchanger, AE2

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 mainta...

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Detalles Bibliográficos
Autores principales: Zhang, Qing, Jian, Liyan, Yao, Deqiang, Rao, Bing, Xia, Ying, Hu, Kexin, Li, Shaobai, Shen, Yafeng, Cao, Mi, Qin, An, Zhao, Jie, Cao, Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10066210/
https://www.ncbi.nlm.nih.gov/pubmed/37002221
http://dx.doi.org/10.1038/s41467-023-37557-y
Descripción
Sumario: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.