Conformational changes required for H(+)/Cl(-) exchange mediated by a CLC transporter.

Nat Struct Mol Biol

1] Department of Anesthesiology, Weill Cornell Medical College, New York, New York, USA. [2] Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York, USA. [3] Department of Biochemistry, Weill Cornell Medical College, New York, New York, USA.

Published: May 2014

CLC-type exchangers mediate transmembrane Cl(-) transport. Mutations altering their gating properties cause numerous genetic disorders. However, their transport mechanism remains poorly understood. In conventional models, two gates alternatively expose substrates to the intra- or extracellular solutions. A glutamate was identified as the only gate in the CLCs, suggesting that CLCs function by a nonconventional mechanism. Here we show that transport in CLC-ec1, a prokaryotic homolog, is inhibited by cross-links constraining movement of helix O far from the transport pathway. Cross-linked CLC-ec1 adopts a wild-type-like structure, indicating stabilization of a native conformation. Movements of helix O are transduced to the ion pathway via a direct contact between its C terminus and a tyrosine that is a constitutive element of the second gate of CLC transporters. Therefore, the CLC exchangers have two gates that are coupled through conformational rearrangements outside the ion pathway.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040230PMC
http://dx.doi.org/10.1038/nsmb.2814DOI Listing

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