Affiliation:
1. Laboratory of Molecular Neurobiology and Biophysics, Howard Hughes Medical Institute, The Rockefeller University, New York, 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.
Funder
Howard Hughes Medical Institute
Jane Coffin Childs Memorial Fund for Medical Research
Charles H. Revson Foundation
Publisher
eLife Sciences Publications, Ltd
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
Cited by
90 articles.
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