Divergent Cl− and H+ pathways underlie transport coupling and gating in CLC exchangers and channels Article Swipe
Lilia Leisle
,
Yanyan Xu
,
Eva Fortea
,
Jason D. Galpin
,
Malvin Vien
,
Christopher A. Ahern
,
Alessio Accardi
,
Simon Bernèche
·
YOU?
·
· 2019
· Open Access
·
· DOI: https://doi.org/10.1101/753954
YOU?
·
· 2019
· Open Access
·
· DOI: https://doi.org/10.1101/753954
The CLC family of anion transporting proteins is comprised of secondary active H + -coupled exchangers and of Cl − channels. Both functional subtypes play key roles in human physiology, and mutations causing their dysfunction lead to numerous genetic disorders. Current models suggest that the CLC exchangers do not utilize a classical ‘ping-pong’ mechanism of antiport, where the transporter sequentially interacts with one substrate at a time. Rather, in the CLC exchangers both substrates bind and translocate simultaneously while moving through partially congruent pathways. How ions of opposite electrical charge bypass each other while moving in opposite directions through a shared permeation pathway remains unknown. Here, we use MD simulations in combination with biochemical and electrophysiological measurements to identify a pair of highly conserved phenylalanine residues that form an aromatic pathway, separate from the Cl − pore, whose dynamic rearrangements enable H + movement. Mutations of these aromatic residues impair H + transport and voltage-dependent gating in the CLC exchangers. Remarkably, the role of the aromatic pathway is evolutionarily conserved in CLC channels. Using atomic-scale mutagenesis we show that the electrostatic properties and conformational flexibility of these aromatic residues are essential determinants of channel gating. Our results suggest that Cl − and H + move through physically distinct and evolutionarily conserved routes through the CLC channels and transporters. We propose a unifying mechanism that describes the gating mechanism of CLC exchangers and channels.
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/753954
- https://www.biorxiv.org/content/biorxiv/early/2019/09/05/753954.full.pdf
- OA Status
- green
- References
- 60
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W2971858961
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W2971858961Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/753954Digital Object Identifier
- Title
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Divergent Cl− and H+ pathways underlie transport coupling and gating in CLC exchangers and channelsWork title
- Type
-
preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
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2019Year of publication
- Publication date
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2019-09-05Full publication date if available
- Authors
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Lilia Leisle, Yanyan Xu, Eva Fortea, Jason D. Galpin, Malvin Vien, Christopher A. Ahern, Alessio Accardi, Simon BernècheList of authors in order
- Landing page
-
https://doi.org/10.1101/753954Publisher landing page
- PDF URL
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https://www.biorxiv.org/content/biorxiv/early/2019/09/05/753954.full.pdfDirect link to full text PDF
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YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
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https://www.biorxiv.org/content/biorxiv/early/2019/09/05/753954.full.pdfDirect OA link when available
- Concepts
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Gating, Chemistry, Antiporter, Biophysics, Transporter, Ion channel, Ion transporter, Coupling (piping), Stereochemistry, Biochemistry, Membrane, Biology, Gene, Materials science, Receptor, MetallurgyTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
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60Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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