Abstract
Anion Exchanger 1 (AE1, SLC4A1) is the primary bicarbonate (HCO3-) transporter expressed in erythrocyte membranes where it mediates transport of CO2 between lungs and other tissues via import/export of bicarbonate. It is also a key regulator of erythrocyte structure and antigenic recognition. Previous biochemical studies, and a low-resolution crystal structure of the transmembrane domain have provided initial insight into AE1 structure and function. However, key questions remain regarding substrate binding and transport as well as the mechanism of inhibition. The orientation of the intracellular domain as well as the localization of lipid and sterol binding sites also remain enigmatic. We herein present seven novel high resolution cryo-EM structures of the full length human transporter in the apo, bicarbonate-bound, and several inhibitor-bound states combined with uptake- and computational studies. To our knowledge, these studies represent the first full length human, and substrate bound, SLC4 transporter structure. Our results reveal important molecular details about substrate binding and transport, as well as the diverse mechanisms of AE1 inhibition by both research chemicals and prescription drugs. We also provide novel insights into the full-length transporter architecture, identify the conformational space of the Diego blood antigen system and elucidate multiple lipid and sterol binding sites.
Competing Interest Statement
The authors have declared no competing interest.
