Transport mechanism of the SLC4 proteins – lessons from recent structural and computational studies

‾, borate, and other ions, necessary for pH maintenance and ion homeostasis. Dysfunction in SLC4 members has been related to debilitating disease states in humans and impaired crop growth. The SLC4 proteins feature uncharacteristically high transport rates and multiple transport modes (cation-anion symport and cation-dependent and independent anion exchange) achieved through small sequence differences in key protein structure areas. This has made them an object of ever-increasing scientific interest. In the last 10 years, multiple X-ray or cryogenic electron microscopy SLC4 structures of members of the family have become available and this prompted computational modelling of various aspects of their function. Structures in outward facing, occluded, and inward facing conformational states showed that the SLC4 transporters use an elevator transport mechanism with small vertical translocation and protein reorganization. Binding sites for ion, lipid, and inhibitors were identified in several members of the family and provided insights into SLC4 functional regulation and the differences between the cation dependent and independent modes of transport. SLC4 structures in complexes with intracellular proteins revealed how protein-protein interactions impact the overall structure of the anion exchanger 1 of the SLC4 family and the relative position of its cytoplasmic and transmembrane domains. In this review we aim to gather these new structural and computational insights, put them in the context of SLC4 transport mechanism, and suggest areas of research that would benefit from further structural, functional, and computational work.