Solute carrier family 26 member a2 (Slc26a2) protein functions as an electroneutral SO 42-/OH -/Cl - exchanger regulated by extracellular Cl -

Abstract

Slc26a2 is a ubiquitously expressed SO 42- transporter with high expression levels in cartilage and several epithelia. Mutations in SLC26A2 are associated with diastrophic dysplasia. The mechanism by which Slc26a2 transports SO 42- and the ion gradients that mediate SO 42- uptake are poorly understood. We report here that Slc26a2 functions as an SO 42-/2OH -, SO 42-/2Cl -, and SO 42-/OH -/Cl - exchanger, depending on the Cl - and OH - gradients. At inward Cl - and outward pH gradients (high Cl -o and low pH o) Slc26a2 functions primarily as an SO 42-o/2OH -i exchanger. At low Cl -o and high pH o Slc26a2 functions increasingly as an SO 42-o/2Cl -i exchanger. The reverse is observed for SO 42-i/2OH -o and SO 42-i/2Cl -o exchange. Slc26a2 also exchanges Cl - for I -, Br -, and NO 3- and Cl -o competes with SO 42- on the transport site. Interestingly, Slc26a2 is regulated by an extracellular anion site, required to activate SO 42-i/2OH -o exchange. Slc26a2 can transport oxalate in exchange for OH - and/or Cl - with properties similar to SO 42- transport. Modeling of the Slc26a2 transmembrane domain (TMD) structure identified a conserved extracellular sequence 367GFXXP 371between TMD7 and TMD8 close to the conserved Glu 417 in the permeation pathway. Mutation of Glu 417 eliminated transport by Slc26a2, whereas mutation of Phe 368 increased the affinity for SO 42-o 8-fold while reducing the affinity for Cl -o 2 fold, but without affecting regulation by Cl -o. These findings clarify the mechanism of net SO 42- transport and describe a novel regulation of Slc26a2 by an extracellular anion binding site and should help in further understanding aberrant SLC26A2 function in diastrophic dysplasia.