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Structure paper

TitleStructural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 6654, Year 2024
Publish dateAug 6, 2024
AuthorsYangzhuoqun 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 /
PubMed AbstractThe 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 ...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.
External linksNat Commun / PubMed:39107281 / PubMed Central
MethodsEM (single particle)
Resolution2.98 - 4.04 Å
Structure data

36200

8jev

EMDB-36200, PDB-8jev:
Cryo-EM structure of apo state mClC-3
Method: EM (single particle) / Resolution: 3.06 Å

36236

8jgj

EMDB-36236, PDB-8jgj:
Cryo-EM structure of mClC-3 with ATP
Method: EM (single particle) / Resolution: 3.3 Å

36237

8jgk

EMDB-36237, PDB-8jgk:
Cryo-EM structure of mClC-3 with ADP
Method: EM (single particle) / Resolution: 4.04 Å

36238

8jgl

EMDB-36238, PDB-8jgl:
Cryo-EM structure of mClC-3 with AMP
Method: EM (single particle) / Resolution: 3.14 Å

36245

8jgs

EMDB-36245, PDB-8jgs:
Cryo-EM structure of apo state mClC-3_I607T
Method: EM (single particle) / Resolution: 3.96 Å

36246

8jgv

EMDB-36246, PDB-8jgv:
Cryo-EM structure of mClC-3_I607T with ATP
Method: EM (single particle) / Resolution: 2.98 Å

Chemicals

ChemComp-CL:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

ChemComp-AMP:
ADENOSINE MONOPHOSPHATE / AMP*YM

Source
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN

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