Structure of the CLC-1 chloride channel from Homo sapiens

Abstract
Data availability
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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.

The following data sets were generated

1. Eunyong Park
2. Roderick MacKinnon
(2018) Human CLC-1 chloride ion channel, transmembrane domain
Publicly available at the RCSB Protein Data Bank (accession no. 6COY).

http://www.rcsb.org/pdb/search/structid-Search.do?structureId=6COY
1. Eunyong Park
2. Roderick MacKinnon
(2018) Human CLC-1 chloride ion channel, C-terminal cytosolic domain
Publicly available at the RCSB Protein Data Bank (accession no. 6COZ).

http://www.rcsb.org/pdb/search/structid-Search.do?structureId=6COZ
1. Eunyong Park
2. Roderick MacKinnon
(2018) Human CLC-1 chloride ion channel, transmembrane domain
Publicly available at the Electron Microscopy Data Bank (accession no. EMD-7544).

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-7544
1. Eunyong Park
2. Roderick MacKinnon
(2018) Human CLC-1 chloride ion channel, C-terminal cytosolic domain
Publicly available at the Electron Microscopy Data Bank (accession no. EMD-7545).

http://www.ebi.ac.uk/pdbe/entry/emdb/EMD-7545

Article and author information

Author details

Eunyong Park

Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Roderick MacKinnon

Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, New York, United States

For correspondence
mackinn@mail.rockefeller.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7605-4679

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

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.