Structural model of the anion exchanger 1 (SLC4A1) and identification of transmembrane segments forming the transport site.

International audienceThe anion exchanger 1 (AE1), member of bicarbonate transporter family SLC4, mediates an electroneutral chloride/bicarbonate exchange in physiological conditions. However, some point mutations in AE1 membrane spanning domain convert the electroneutral anion exchanger into a Na+ and K+ conductance or induce a cation leak in a still functional anion exchanger. The molecular determinants that govern ion movement through this transporter are still unknown. The present study was intended to identify the ion translocation pathway within AE1. In the absence of resolutive 3D structure of AE1 membrane spanning domain, in silico modeling combined with site directed mutagenesis experiments have been done. A structural model of AE1 membrane spanning domain is proposed and this model is based on the structure of Uracil-proton symporter. This model was used to design cysteine-scanning mutagenesis on transmembrane segments (TM) 3 and 5. By measuring AE1 anion exchange activity or cation leak it is proposed that there is a unique transport site comprising TM3-5 and 8 that should function as an anion exchanger and a cation leak