Structural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger

Yangzhuoqun Wan, Shuangshuang Guo, Wenxuan Zhen, Lizhen Xu, Xiaoying Chen, Fangyue Liu, Yi Shen, Shuangshuang Liu, Lidan Hu, Xinyan Wang, Fengcan Ye, Qinrui Wang, Han Wen () and Fan Yang ()
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Yangzhuoqun Wan: Zhejiang University School of Medicine
Shuangshuang Guo: Zhejiang University School of Medicine
Wenxuan Zhen: Zhejiang University School of Medicine
Lizhen Xu: Zhejiang University School of Medicine
Xiaoying Chen: Zhejiang University School of Medicine
Fangyue Liu: Zhejiang University School of Medicine
Yi Shen: Zhejiang University School of Medicine
Shuangshuang Liu: Zhejiang University School of Medicine
Lidan Hu: National Clinical Research Center for Child Health
Xinyan Wang: DP Technology
Fengcan Ye: DP Technology
Qinrui Wang: DP Technology
Han Wen: DP Technology
Fan Yang: Zhejiang University School of Medicine

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

Abstract: Abstract The ClC-3 chloride/proton exchanger is both physiologically and pathologically critical, as it is potentiated by ATP to detect metabolic energy level and point mutations in ClC-3 lead to severe neurodegenerative diseases in human. However, why this exchanger is differentially modulated by ATP, ADP or AMP and how mutations caused gain-of-function remains largely unknow. Here we determine the high-resolution structures of dimeric wildtype ClC-3 in the apo state and in complex with ATP, ADP and AMP, and the disease-causing I607T mutant in the apo and ATP-bounded state by cryo-electron microscopy. In combination with patch-clamp recordings and molecular dynamic simulations, we reveal how the adenine nucleotides binds to ClC-3 and changes in ion occupancy between apo and ATP-bounded state. We further observe I607T mutation induced conformational changes and augments in current. Therefore, our study not only lays the structural basis of adenine nucleotides regulation in ClC-3, but also clearly indicates the target region for drug discovery against ClC-3 mediated neurodegenerative diseases.

Date: 2024
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DOI: 10.1038/s41467-024-50975-w

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