Transport mechanism of the SLC4 proteins-Lessons from recent structural and computational studies

The solute carrier family 4 (SLC4) secondary transporters are found ubiquitously in animal, plant, and fungal tissues, where they transport HCO₃^-, CO₃^2-, borate, and other ions, necessary for pH maintenance and ion homeostasis. Dysfunction in SLC4 members has been related to debilitating human diseases and impaired crop growth. SLC4 proteins feature high transport rates and multiple transport modes (cation-anion symport and cation-dependent and -independent anion exchange) achieved through small sequence differences in key structural regions of the protein. This has made them a subject of increasing scientific interest. In the last decade, X-ray and cryogenic electron microscopy structures of SLC4 members have become available, prompting computational modeling of their function. Structures of selected SLC4 members in outward facing, occluded/intermediate, and inward facing conformations, together with computational modelling support an elevator transport mechanism with small vertical translocation and protein reorganization. However, inward-facing structures of the Na⁺-dependent SLC4 transporters and true intermediate experimental structures for all mammalian SLC4 members have not yet been determined. Binding sites for ions, lipids, and inhibitors were identified in several family members, providing insights into regulation and the differences between the cation-dependent and -independent transport. SLC4 complexes with intracellular proteins revealed how protein-protein interactions impact the structure of anion exchanger 1 and the relative position of its cytoplasmic and transmembrane domains. This review summarizes these structural and computational insights, places them in the context of the SLC4 transport mechanism, and highlights questions for further structural, functional, and computational studies.