Asymmetric pendrin homodimer reveals its molecular mechanism as anion exchanger

Qianying Liu; Xiang Zhang; Hui Huang; Yuxin Chen; Fang Wang; Aihua Hao; Wuqiang Zhan; Qiyu Mao; Yuxia Hu; Lin Han; Yifang Sun; Meng Zhang; Zhimin Liu; Geng-Lin Li; Weijia Zhang; Yilai Shu; Lei Sun; Zhenguo Chen

doi:10.1038/s41467-023-38303-0

Asymmetric pendrin homodimer reveals its molecular mechanism as anion exchanger

Nat Commun. 2023 May 25;14(1):3012. doi: 10.1038/s41467-023-38303-0.

Authors

Qianying Liu^#¹, Xiang Zhang^#¹, Hui Huang^#¹, Yuxin Chen^#^{2

3

4}, Fang Wang^{2

3

4}, Aihua Hao¹, Wuqiang Zhan¹, Qiyu Mao¹, Yuxia Hu¹, Lin Han¹, Yifang Sun¹, Meng Zhang¹, Zhimin Liu¹, Geng-Lin Li^{2

3

4}, Weijia Zhang¹, Yilai Shu^{5

6

7

8}, Lei Sun^{9

10

11}, Zhenguo Chen^{12

13

14}

Affiliations

¹ The Fifth People's Hospital of Shanghai and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
² ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200031, China.
³ MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, China.
⁴ NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, 200031, China.
⁵ ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200031, China. yilai_shu@fudan.edu.cn.
⁶ MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200031, China. yilai_shu@fudan.edu.cn.
⁷ NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, 200031, China. yilai_shu@fudan.edu.cn.
⁸ Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. yilai_shu@fudan.edu.cn.
⁹ The Fifth People's Hospital of Shanghai and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. llsun@fudan.edu.cn.
¹⁰ Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, 200032, China. llsun@fudan.edu.cn.
¹¹ Shanghai Key Laboratory of Medical Epigenetics, Shanghai, 200032, China. llsun@fudan.edu.cn.
¹² The Fifth People's Hospital of Shanghai and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China. zhenguochen@fudan.edu.cn.
¹³ Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, 200032, China. zhenguochen@fudan.edu.cn.
¹⁴ Shanghai Key Laboratory of Medical Epigenetics, Shanghai, 200032, China. zhenguochen@fudan.edu.cn.

^# Contributed equally.

Abstract

Pendrin (SLC26A4) is an anion exchanger expressed in the apical membranes of selected epithelia. Pendrin ablation causes Pendred syndrome, a genetic disorder associated with sensorineural hearing loss, hypothyroid goiter, and reduced blood pressure. However its molecular structure has remained unknown, limiting our understanding of the structural basis of transport. Here, we determine the cryo-electron microscopy structures of mouse pendrin with symmetric and asymmetric homodimer conformations. The asymmetric homodimer consists of one inward-facing protomer and the other outward-facing protomer, representing coincident uptake and secretion- a unique state of pendrin as an electroneutral exchanger. The multiple conformations presented here provide an inverted alternate-access mechanism for anion exchange. The structural and functional data presented here disclose the properties of an anion exchange cleft and help understand the importance of disease-associated variants, which will shed light on the pendrin exchange mechanism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anions
Cryoelectron Microscopy
Goiter, Nodular* / genetics
Membrane Transport Proteins* / genetics
Mice
Protein Subunits
Sulfate Transporters / genetics

Substances

Protein Subunits
Membrane Transport Proteins
Sulfate Transporters
Anions