| Structural highlights
Function
CLCN3_MOUSE May influence large dense-core vesicle exocytosis in adrenal chromaffin cells.[1] Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons (PubMed:26342074). The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons (By similarity). The presence of conserved gating glutamate residues is typical for family members that function as antiporters (By similarity).[UniProtKB:P51790][2] Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons (PubMed:24603049, PubMed:26342074, PubMed:28972156). Facilitates endosomal acidification and chloride accumulation in hepatocytes (PubMed:15504734).[3] [4] [5] [6] Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons.[7]
Publication Abstract from PubMed
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.
Structural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger.,Wan Y, Guo S, Zhen W, Xu L, Chen X, Liu F, Shen Y, Liu S, Hu L, Wang X, Ye F, Wang Q, Wen H, Yang F Nat Commun. 2024 Aug 6;15(1):6654. doi: 10.1038/s41467-024-50975-w. PMID:39107281[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Guzman RE, Miranda-Laferte E, Franzen A, Fahlke C. Neuronal ClC-3 Splice Variants Differ in Subcellular Localizations, but Mediate Identical Transport Functions. J Biol Chem. 2015 Oct 23;290(43):25851-62. PMID:26342074 doi:10.1074/jbc.M115.668186
- ↑ Hara-Chikuma M, Yang B, Sonawane ND, Sasaki S, Uchida S, Verkman AS. ClC-3 chloride channels facilitate endosomal acidification and chloride accumulation. J Biol Chem. 2005 Jan 14;280(2):1241-7. PMID:15504734 doi:10.1074/jbc.M407030200
- ↑ Okada T, Akita T, Sato-Numata K, Islam MR, Okada Y. A newly cloned ClC-3 isoform, ClC-3d, as well as ClC-3a mediates Cd-sensitive outwardly rectifying anion currents. Cell Physiol Biochem. 2014;33(3):539-56. PMID:24603049 doi:10.1159/000358633
- ↑ Guzman RE, Miranda-Laferte E, Franzen A, Fahlke C. Neuronal ClC-3 Splice Variants Differ in Subcellular Localizations, but Mediate Identical Transport Functions. J Biol Chem. 2015 Oct 23;290(43):25851-62. PMID:26342074 doi:10.1074/jbc.M115.668186
- ↑ Guzman RE, Bungert-Plümke S, Franzen A, Fahlke C. Preferential association with ClC-3 permits sorting of ClC-4 into endosomal compartments. J Biol Chem. 2017 Nov 17;292(46):19055-19065. PMID:28972156 doi:10.1074/jbc.M117.801951
- ↑ Guzman RE, Miranda-Laferte E, Franzen A, Fahlke C. Neuronal ClC-3 Splice Variants Differ in Subcellular Localizations, but Mediate Identical Transport Functions. J Biol Chem. 2015 Oct 23;290(43):25851-62. PMID:26342074 doi:10.1074/jbc.M115.668186
- ↑ Wan Y, Guo S, Zhen W, Xu L, Chen X, Liu F, Shen Y, Liu S, Hu L, Wang X, Ye F, Wang Q, Wen H, Yang F. Structural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger. Nat Commun. 2024 Aug 6;15(1):6654. PMID:39107281 doi:10.1038/s41467-024-50975-w
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