Divergent Cl and H pathways underlie transport coupling and gating in CLC exchangers and channels.

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.

Probing the conformation of a conserved glutamic acid within the Cl pathway of a CLC H/Cl exchanger.

The CLC proteins form a broad family of anion-selective transport proteins that includes both channels and exchangers. Despite extensive structural, functional, and computational studies, the transport mechanism of the CLC exchangers remains poorly understood. Several transport models have been proposed but have failed to capture all the key features of these transporters.