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.
Data availability
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
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