Divergent Cl-and H+ pathways underlie transport coupling and gating in CLC exchangers and channels
- Weill Cornell Medical College, United States
- University of Basel, Switzerland
- University of Iowa Carver College of Medicine, United States
Abstract
The CLC family comprises H+-coupled exchangers and Cl- channels, and mutations causing their dysfunction lead to genetic disorders. The CLC exchangers, unlike canonical 'ping-pong' antiporters, simultaneously bind and translocate substrates through partially congruent pathways. How ions of opposite charge bypass each other while moving through a shared pathway remains unknown. Here, we use MD simulations, biochemical and electrophysiological measurements to identify two conserved phenylalanine residues that form an aromatic pathway whose dynamic rearrangements enable H+ movement outside the Cl- pore. These residues are important for H+ transport and voltage-dependent gating in the CLC exchangers. The aromatic pathway residues are evolutionarily conserved in CLC channels where their electrostatic properties and conformational flexibility determine gating. We propose that Cl- and H+ move through physically distinct and evolutionarily conserved routes through the CLC channels and transporters and suggest a unifying mechanism that describes the gating mechanism of both CLC subtypes.
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All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Christopher A Ahern
Funding
National Institutes of Health (GM128420)
- Alessio Accardi
National Institutes of Health (NS104617)
- Christopher A Ahern
SNF (No PP00P3_139205)
- Simon Bernèche
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Leisle et al.
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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Divergent Cl-and H+ pathways underlie transport coupling and gating in CLC exchangers and channels
eLife 9:e51224.
https://doi.org/10.7554/eLife.51224
