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Philos Trans R Soc Lond B Biol Sci. 2009 Jan 27;364(1514):175-80. doi: 10.1098/rstb.2008.0138.

A provisional transport mechanism for a chloride channel-type Cl-/H+ exchanger.

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Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, MA 02454, USA.


Chloride channel (CLC)-type Cl-/H+ exchangers are widespread throughout the biological world, and one of these, CLC-ec1 from Escherichia coli, has been extensively studied. The structure of this protein is known, and several of its mechanistic hot spots have been identified, but a mechanism for Cl-/H+ exchange has not previously been offered. We herein confirm by direct measurements of Cl- and H+ fluxes a Cl--to-H+ exchange stoichiometry of 2, and summarize experimental facts pertinent to the exchange mechanism. While the mechanism must involve a conformational cycle of alternating exposure of substrate-binding sites to the two sides of the membrane, CLC transporters do not adhere to a familiar ping-pong scheme in which the two ions bind in a mutually exclusive fashion. Instead, Cl- and H+ occupy the ion-binding region simultaneously. A conformational cycle is proposed that accounts for the exchange stoichiometry, several key mutants and the tendency of the protein to become uncoupled and allow 'slippage' of Cl-.

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