ArticleProceedings of the National Academy of Sciences of the United States of America2014
Water access points and hydration pathways in CLC H+/Cl- transporters.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 62 citations in OpenAlex.
- Molecular mechanism of exchange coupling in CLC chloride/proton antiporters.Nature communications · 2026Article
- Mechanism of phosphoinositide regulation of lysosomal pH via inhibition of CLC-7.bioRxiv : the preprint server for biology · 2025Article
- Structural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger.Nature communications · 2024Article
- Structural basis of pH-dependent activation in a CLC transporter.Nature structural & molecular biology · 2024Article
- Fluoride Ion Binding and Translocation in the CLCThe journal of physical chemistry. B · 2024Article
- Review
- Anionic omega currents from single countercharge mutants in the voltage-sensing domain of Ci-VSP.The Journal of general physiology · 2024Article
- Fluoride Transport and Inhibition Across CLC Transporters.Handbook of experimental pharmacology · 2024Article
- The role of conformational change and key glutamic acid residues in the ClC-ec1 antiporter.Biophysical journal · 2023Article
- Vesicular CLC chloride/proton exchangers in health and diseases.Frontiers in pharmacology · 2023Review
- Mechanism of voltage gating in the voltage-sensing phosphatase Ci-VSP.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- The Role of the Lysosomal ClCells · 2022Review
- Simulation of pH-Dependent Conformational Transitions in Membrane Proteins: The CLC-ec1 ClMolecules (Basel, Switzerland) · 2021Article
- Molecular mechanism of proton-coupled ligand translocation by the bacterial efflux pump EmrE.PLoS computational biology · 2021Article
- Toward a Multipathway Perspective: pH-Dependent Kinetic Selection of Competing Pathways and the Role of the Internal Glutamate in ClThe journal of physical chemistry. B · 2021Article
- Cryo-EM structure of the lysosomal chloride-proton exchanger CLC-7 in complex with OSTM1.eLife · 2020Article
- A CLC-ec1 mutant reveals global conformational change and suggests a unifying mechanism for the CLC CleLife · 2020Article
- Local conformational dynamics regulating transport properties of a ClJournal of computational chemistry · 2020Article
- Computational Dissection of Membrane Transport at a Microscopic Level.Trends in biochemical sciences · 2020Review
- Mutation of external glutamate residue reveals a new intermediate transport state and anion binding site in a CLC ClProceedings of the National Academy of Sciences of the United States of America · 2019Article
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4 authors at 2 institutions in 1 country.
Funding
Abstract
CLC transporters catalyze transmembrane exchange of chloride for protons. Although a putative pathway for Cl(-) has been established, the pathway of H(+) translocation remains obscure. Through a highly concerted computational and experimental approach, we characterize microscopic details essential to understanding H(+)-translocation. An extended (0.4 µs) equilibrium molecular dynamics simulation of membrane-embedded, dimeric ClC-ec1, a CLC from Escherichia coli, reveals transient but frequent hydration of the central hydrophobic region by water molecules from the intracellular bulk phase via the interface between the two subunits. We characterize a portal region lined by E202, E203, and A404 as the main gateway for hydration. Supporting this mechanism, site-specific mutagenesis experiments show that ClC-ec1 ion transport rates decrease as the size of the portal residue at position 404 is increased. Beyond the portal, water wires form spontaneously and repeatedly to span the 15-Å hydrophobic region between the two known H(+) transport sites [E148 (Glu(ex)) and E203 (Glu(in))]. Our finding that the formation of these water wires requires the presence of Cl(-) explains the previously mystifying fact that Cl(-) occupancy correlates with the ability to transport protons. To further validate the idea that these water wires are central to the H(+) transport mechanism, we identified I109 as the residue that exhibits the greatest conformational coupling to water wire formation and experimentally tested the effects of mutating this residue. The results, by providing a detailed microscopic view of the dynamics of water wire formation and confirming the involvement of specific protein residues, offer a mechanism for the coupled transport of H(+) and Cl(-) ions in CLC transporters.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.