The structural insight into the functional modulation of human anion exchanger 3

• Published in: Nature communications Vol. 15; no. 1; pp. 6134 - 13
• Main Authors: Jian, Liyan, Zhang, Qing, Yao, Deqiang, Wang, Qian, Chen, Moxin, Xia, Ying, Li, Shaobai, Shen, Yafeng, Cao, Mi, Qin, An, Li, Lin, Cao, Yu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.07.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid - pharmacology; 631/45/612/1237; 631/535/1258/1259; 631/92/577; 82/29; 82/80; 82/83; Alkalosis; Anion exchanging; Antiporters - chemistry; Antiporters - ultrastructure; Binding Sites; Chimeras; Conformation; Cryoelectron Microscopy; Detergents; Dynamic structural analysis; Electron microscopy; Genes; HEK293 Cells; Homeostasis; Humanities and Social Sciences; Humans; Hydrogen-Ion Concentration; Medicine; Metabolism; Models, Molecular; multidisciplinary; Mutation; Orthopedics; pH effects; Protein Conformation; Protein Domains; Science; Science (multidisciplinary); Sensitivity enhancement; Sodium; Structure-function relationships; Substrates; Transmembrane domains
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50572-x

Anion exchanger 3 (AE3) is pivotal in regulating intracellular pH across excitable tissues, yet its structural intricacies and functional dynamics remain underexplored compared to other anion exchangers. This study unveils the structural insights into human AE3, including the cryo-electron microscopy structures for AE3 transmembrane domains (TMD) and a chimera combining AE3 N-terminal domain (NTD) with AE2 TMD (hAE3 NTD 2 TMD ). Our analyzes reveal a substrate binding site, an NTD-TMD interlock mechanism, and a preference for an outward-facing conformation. Unlike AE2, which has more robust acid-loading capabilities, AE3’s structure, including a less stable inward-facing conformation due to missing key NTD-TMD interactions, contributes to its moderated pH-modulating activity and increased sensitivity to the inhibitor DIDS. These structural differences underline AE3’s distinct functional roles in specific tissues and underscore the complex interplay between structural dynamics and functional specificity within the anion exchanger family, enhancing our understanding of the physiological and pathological roles of the anion exchanger family. This study provides structural insights into human AE3’s role in pH regulation in excitable tissues, highlighting its structural differences from AE2 in anion transport regulation and their sensitivity to inhibitors.