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Nat Struct Mol Biol. 2014 May;21(5):456-63. doi: 10.1038/nsmb.2814. Epub 2014 Apr 20.

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

Author information

1
Department of Anesthesiology, Weill Cornell Medical College, New York, New York, USA.
2
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.

Abstract

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.

PMID:
24747941
PMCID:
PMC4040230
DOI:
10.1038/nsmb.2814
[Indexed for MEDLINE]
Free PMC Article

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