Divergent Cl- and H+ pathways underlie transport coupling and gating in CLC exchangers and channels
| Autor: | Simon Bernèche, Eva Fortea, Sangyun Lee, Alessio Accardi, Jason D. Galpin, Malvin Vien, Lilia Leisle, Christopher A. Ahern, Yanyan Xu |
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| Rok vydání: | 2020 |
| Předmět: |
QH301-705.5
Science Xenopus Chemical biology Gating General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine active transport membrane protein Biology (General) Ion channel 030304 developmental biology 0303 health sciences General Immunology and Microbiology biology urogenital system Chemistry General Neuroscience ion channels General Medicine biology.organism_classification Antiporters 3. Good health Coupling (electronics) Membrane protein Structural biology Biophysics Medicine ddc:600 030217 neurology & neurosurgery |
| Zdroj: | eLife, Vol 9 (2020) eLife 9, e51224 (2020). doi:10.7554/eLife.51224 |
| ISSN: | 2050-084X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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