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.
Highlights
The CLC (ChLoride Channel) family is comprised of Cl- channels and H+-coupled exchangers whose primary physiological task is to mediate anion transport across biological membranes (Accardi, 2015; Jentsch and Pusch, 2018)
Our results suggest that the aromatic slide formed by Phecen and Pheex forms an evolutionarily conserved structural motif that enables movement of Gluex in and out of the Cl- pore during the exchange cycle and gating of CLC exchangers and opening of CLC channels
The recent structures of the CLCF exchanger and of the CLC-1 Cl- channel suggested that Gluex might interact with Phecen (Last et al, 2018; Park and MacKinnon, 2018), but the functional implications of these interactions are not clear
Summary
The CLC (ChLoride Channel) family is comprised of Cl- channels and H+-coupled exchangers whose primary physiological task is to mediate anion transport across biological membranes (Accardi, 2015; Jentsch and Pusch, 2018). Several disease-causing mutations occurring in CLC channels and transporters impair the response to the physiological stimuli regulating their activity, such as voltage, pH and nucleotide concentration (Accardi, 2015; Alekov, 2015; Bignon et al, 2018; Jentsch and Pusch, 2018). High-resolution structural information on the CLC-ec and cmCLC exchangers (Dutzler et al, 2002; Feng et al, 2010) as well as CLC-K and CLC-1 channels
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