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

Liyan Jian, Qing Zhang, Deqiang Yao, Qian Wang, Moxin Chen, Ying Xia, Shaobai Li, Yafeng Shen, Mi Cao, An Qin (), Lin Li () and Yu Cao ()
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Liyan Jian: Shanghai Jiao Tong University School of Medicine
Qing Zhang: Shanghai Jiao Tong University School of Medicine
Deqiang Yao: Shanghai Jiao Tong University School of Medicine
Qian Wang: Shanghai Jiao Tong University School of Medicine
Moxin Chen: Shanghai Jiao Tong University
Ying Xia: 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
Lin Li: Shanghai Jiao Tong University
Yu Cao: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract 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 (hAE3NTD2TMD). 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.

Date: 2024
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DOI: 10.1038/s41467-024-50572-x

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