Structure of a CLC-Family Fluoride/Proton Antiporter

The CLC superfamily of anion transporters and channels has been studied for decades, but large swaths of the superfamily remain unexamined. One of those unstudied branches was recently found to be a family of fluoride/proton antiporters (CLCF), evolved to protect bacteria against intracellular fluoride accumulation. In addition to the clearly altered selectivity, these transporters also have a different transport stoichiometry from the chloride transporters (1 F- / 1 proton, vs 2 Cl- / 1 proton), suggesting a change in the transport mechanism. We have crystallized and solved the structure of CLCF-Eca, the fluoride CLC from Enterococcus casseliflavus, in complex with monobody crystallization chaperones at 3.28 A. To our knowledge this is the first structure of a fluoride CLC, and also the first structure of a non-chloride CLC-transporter. While some critical functional elements from the chloride CLCs remain, such as the external glutamate gate, other regions involved in both selectivity and ion coupling have been significantly altered.