Structural and functional insights into the lipid regulation of human anion exchanger 2

• Published in: Nature communications Vol. 15; no. 1; pp. 759 - 10
• Main Authors: Zhang, Weiqi, Ding, Dian, Lu, Yishuo, Chen, Hongyi, Jiang, Peijun, Zuo, Peng, Wang, Guangxi, Luo, Juan, Yin, Yue, Luo, Jianyuan, Yin, Yuxin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.01.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 13/1; 13/31; 14/19; 14/35; 631/45/612/1222; 631/535/1258/1259; 631/57/2283; 692/699; 82/80; 82/83; Anion exchanging; Binding sites; Conformation; Humanities and Social Sciences; Lipids; multidisciplinary; Osteoclastogenesis; Phosphatidylinositol 4,5-diphosphate; Regulation; Regulatory mechanisms (biology); Science; Science (multidisciplinary); Structure-function relationships; Substrates; Transmembrane domains
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-44966-0

Anion exchanger 2 (AE2) is an electroneutral Na + -independent Cl - /HCO 3 - exchanger belongs to the SLC4 transporter family. The widely expressed AE2 participates in a variety of physiological processes, including transepithelial acid-base secretion and osteoclastogenesis. Both the transmembrane domains (TMDs) and the N-terminal cytoplasmic domain (NTD) are involved in regulation of AE2 activity. However, the regulatory mechanism remains unclear. Here, we report a 3.2 Å cryo-EM structure of the AE2 TMDs in complex with PIP 2 and a 3.3 Å full-length mutant AE2 structure in the resting state without PIP 2 . We demonstrate that PIP 2 at the TMD dimer interface is involved in the substrate exchange process. Mutation in the PIP 2 binding site leads to the displacement of TM7 and further stabilizes the interaction between the TMD and the NTD. Reduced substrate transport activity and conformation similar to AE2 in acidic pH indicating the central contribution of PIP 2 to the function of AE2. Anion exchanger 2 (AE2), a widely expressed Cl- /HCO3 - exchanger, participates in the regulation of intracellular pH. Here, the authors present the structures of AE2 and uncover the regulatory mechanism of PIP2.