Structural models of the NaPi-II sodium-phosphate cotransporters

Progress towards understanding the molecular mechanisms of phosphate homeostasis through sodium-dependent transmembrane uptake has long been stymied by the absence of structural information about the NaPi-II sodium-phosphate transporters. For many other coupled transporters, even those unrelated to NaPi-II, internal repeated elements have been revealed as a key feature that is inherent to their function. Here, we review recent structure prediction studies for NaPi-II transporters. Attempts to identify structural templates for NaPi-II transporters have leveraged the structural repeat perspective to uncover an otherwise obscured relationship with the dicarboxylate-sodium symporters (DASS). This revelation allowed the prediction of three-dimensional structural models of human NaPi-IIa and flounder NaPi-IIb, whose folds were evaluated by comparison with available biochemical data outlining the transmembrane topology and solvent accessibility of various regions of the protein. Using these structural models, binding sites for sodium and phosphate were proposed. The predicted sites were tested and refined based on detailed electrophysiological and biochemical studies and were validated by comparison with subsequently reported structures of transporters belonging to the AbgT family. Comparison with the DASS transporter VcINDY suggested a conformational mechanism involving a large, two-domain structural change, known as an elevator-like mechanism. These structural models provide a foundation for further studies into substrate binding, conformational change, kinetics, and energetics of sodium-phosphate transport. We discuss future opportunities, as well as the challenges that remain.