Nature Communications (Aug 2024)

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,
  • Fan Yang

DOI
https://doi.org/10.1038/s41467-024-50975-w
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 13

Abstract

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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.