Journal article
Divergent Cl- and H+ pathways underlie transport coupling and gating in CLC exchangers and channels
eLife, Vol.9, e51224
04/28/2020
DOI: 10.7554/eLife.51224
PMID: 32343228
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.
Details
- Title: Subtitle
- Divergent Cl- and H+ pathways underlie transport coupling and gating in CLC exchangers and channels
- Creators
- Lilia Leisle - Department of Anesthesiology, Weill Cornell Medical College, New York, United StatesYanyan Xu - SIB Swiss Institute of Bioinformatics, University of Basel, Basel, Switzerland, Biozentrum, University of Basel, Basel, SwitzerlandEva Fortea - Department of Physiology and Biophysics, Weill Cornell Medical College, New York, United StatesSangyun Lee - Department of Anesthesiology, Weill Cornell Medical College, New York, United StatesJason D Galpin - Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, United StatesMalvin Vien - Department of Anesthesiology, Weill Cornell Medical College, New York, United StatesChristopher A Ahern - Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, United StatesAlessio Accardi - Department of Anesthesiology, Weill Cornell Medical College, New York, United States, Department of Physiology and Biophysics, Weill Cornell Medical College, New York, United States, Department of Biochemistry, Weill Cornell Medical College, New York, United StatesSimon Bernèche - SIB Swiss Institute of Bioinformatics, University of Basel, Basel, Switzerland, Biozentrum, University of Basel, Basel, Switzerland
- Resource Type
- Journal article
- Publication Details
- eLife, Vol.9, e51224
- DOI
- 10.7554/eLife.51224
- PMID
- 32343228
- NLM abbreviation
- Elife
- ISSN
- 2050-084X
- eISSN
- 2050-084X
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: GM128420; DOI: 10.13039/100000002, name: National Institutes of Health, award: NS104617; DOI: 10.13039/501100001711, name: Swiss National Science Foundation, award: PP00P3_139205; DOI: 10.13039/501100004543, name: China Scholarship Council
- Language
- English
- Date published
- 04/28/2020
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984070286502771
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