Structure of the CLC-1 chloride channel from Homo sapiens
- The Rockefeller University, United States
Abstract
CLC channels mediate passive Cl- conduction, while CLC transporters mediate active Cl- transport coupled to H+ transport in the opposite direction. The distinction between CLC-0/1/2 channels and CLC transporters seems undetectable by amino acid sequence. To understand why they are different functionally we determined the structure of the human CLC-1 channel. Its 'glutamate gate' residue, known to mediate proton transfer in CLC transporters, adopts a location in the structure that appears to preclude it from its transport function. Furthermore, smaller side chains produce a wider pore near the intracellular surface, potentially reducing a kinetic barrier for Cl- conduction. When the corresponding residues are mutated in a transporter, it is converted to a channel. Finally, Cl- at key sites in the pore appear to interact with reduced affinity compared to transporters. Thus, subtle differences in glutamate gate conformation, internal pore diameter and Cl- affinity distinguish CLC channels and transporters.
Data availability
Cryo-EM density maps of human CLC-1 have been deposited in the electron microscopy data bank under accession code EMD-7544 and 7545. Atomic coordinates have been deposited in the protein data bank under accession code 6COY and 6COZ.
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Human CLC-1 chloride ion channel, transmembrane domainPublicly available at the RCSB Protein Data Bank (accession no. 6COY).
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Human CLC-1 chloride ion channel, C-terminal cytosolic domainPublicly available at the RCSB Protein Data Bank (accession no. 6COZ).
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Human CLC-1 chloride ion channel, transmembrane domainPublicly available at the Electron Microscopy Data Bank (accession no. EMD-7544).
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Human CLC-1 chloride ion channel, C-terminal cytosolic domainPublicly available at the Electron Microscopy Data Bank (accession no. EMD-7545).
Article and author information
Author details
Roderick MacKinnon
Funding
Howard Hughes Medical Institute
- Roderick MacKinnon
Jane Coffin Childs Memorial Fund for Medical Research
- Eunyong Park
Charles H. Revson Foundation
- Eunyong Park
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Park & MacKinnon
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structure of the CLC-1 chloride channel from Homo sapiens
eLife 7:e36629.
https://doi.org/10.7554/eLife.36629
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