부산대학교 도서관

The CLC family comprises H.sup.+-coupled exchangers and Cl.sup.- 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.sup.+ movement outside the Cl.sup.- pore. These residues are important for H.sup.+ 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.sup.- and H.sup.+ 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.
Byline: Lilia Leisle, Yanyan Xu, Eva Fortea, Sangyun Lee, Jason D Galpin, Malvin Vien, Christopher A Ahern, Alessio Accardi, Simon Bernèche Introduction The CLC (ChLoride Channel) family is comprised of [...]