Structure of the sodium-dependent phosphate transporter reveals insights into human solute carrier SLC20

Abstract

Inorganic phosphate (P_i) is a fundamental and essential element for nucleotide biosynthesis, energy supply, and cellular signaling in living organisms. Human phosphate transporter (<i>h</i>PiT) dysfunction causes numerous diseases, but the molecular mechanism underlying transporters remains elusive. We report the structure of the sodium-dependent phosphate transporter from <i>Thermotoga maritima</i> (<i>Tm</i>PiT) in complex with sodium and phosphate (<i>Tm</i>PiT-Na/Pi) at 2.3-angstrom resolution. We reveal that one phosphate and two sodium ions (Pi-2Na) are located at the core of <i>Tm</i>PiT and that the third sodium ion (Na_fore) is located near the inner membrane boundary. We propose an elevator-like mechanism for sodium and phosphate transport by <i>Tm</i>PiT, with the <i>Tm</i>PiT-Na/Pi complex adopting an inward occluded conformation. We found that disease-related <i>h</i>PiT variants carry mutations in the corresponding sodium- and phosphate-binding residues identified in <i>Tm</i>PiT. Our three-dimensional structure of <i>Tm</i>PiT provides a framework for understanding PiT dysfunction and for future structure-based drug design.