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

TitleConformational changes required for H(+)/Cl(-) exchange mediated by a CLC transporter.
Publication TypeJournal Article
Year of Publication2014
AuthorsBasilio D, Noack K, Picollo A, Accardi A
JournalNat Struct Mol Biol
Volume21
Issue5
Pagination456-63
Date Published2014 May
ISSN1545-9985
KeywordsBiological Transport, Chloride Channels, Crystallography, X-Ray, Escherichia coli K12, Escherichia coli Proteins, Models, Molecular, Mutation, Protein Structure, Tertiary
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.

DOI10.1038/nsmb.2814
Alternate JournalNat. Struct. Mol. Biol.
PubMed ID24747941
PubMed Central IDPMC4040230
Grant ListGM085232 / GM / NIGMS NIH HHS / United States
R01 GM085232 / GM / NIGMS NIH HHS / United States