Molecular basis for differential anion binding and proton coupling in the Cl-/H+ exchanger ClC-ec1

Tao Jiang, Wei Han, Merritt Maduke, Emad Tajkhorshid

Research output: Contribution to journalArticlepeer-review


Cl-/H+ transporters of the CLC superfamily form a ubiquitous class of membrane proteins that catalyze stoichiometrically coupled exchange of Cl- and H+ across biological membranes. CLC transporters exchange H+ for halides and certain polyatomic anions, but exclude cations, F-, and larger physiological anions, such as PO43- and SO42-. Despite comparable transport rates of different anions, the H+ coupling in CLC transporters varies significantly depending on the chemical nature of the transported anion. Although the molecular mechanism of exchange remains unknown, studies on bacterial ClC-ec1 transporter revealed that Cl- binding to the central anion-binding site (Scen) is crucial for the anion-coupled H+ transport. Here, we show that Cl-, F-, NO3-, and SCN- display distinct binding coordinations at the Scen site and are hydrated in different manners. Consistent with the observation of differential bindings, ClC-ec1 exhibits markedly variable ability to support the formation of the transient water wires, which are necessary to support the connection of the two H+ transfer sites (Gluin and Gluex), in the presence of different anions. While continuous water wires are frequently observed in the presence of physiologically transported Cl-, binding of F- or NO3- leads to the formation of pseudo-water-wires that are substantially different from the wires formed with Cl-. Binding of SCN-, however, eliminates the water wires altogether. These findings provide structural details of anion binding in ClC-ec1 and reveal a putative atomic-level mechanism for the decoupling of H+ transport to the transport of anions other than Cl-.

Original languageEnglish (US)
Pages (from-to)3066-3075
Number of pages10
JournalJournal of the American Chemical Society
Issue number9
StatePublished - Mar 9 2016

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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