Structure of the CLC-1 chloride channel from Homo sapiens

Abstract

CLC channels mediate passive Cl^- conduction, while CLC transporters mediate active Cl^- transport coupled to H⁺ transport in the opposite direction. The distinction between CLC-0/1/2 channels and CLC transporters seems undetectable by amino acid sequence. To understand why they are different functionally we determined the structure of the human CLC-1 channel. Its 'glutamate gate' residue, known to mediate proton transfer in CLC transporters, adopts a location in the structure that appears to preclude it from its transport function. Furthermore, smaller side chains produce a wider pore near the intracellular surface, potentially reducing a kinetic barrier for Cl^- conduction. When the corresponding residues are mutated in a transporter, it is converted to a channel. Finally, Cl^- at key sites in the pore appear to interact with reduced affinity compared to transporters. Thus, subtle differences in glutamate gate conformation, internal pore diameter and Cl^- affinity distinguish CLC channels and transporters.