2020同步年報

044 ACTIVITY REPORT 2020 M aintaining Pi balance is essential for the growth and development of all organisms; membrane-bound phosphate transporters are key factors in sustaining Pi homeostasis in humans, plants, fungi and bacteria. In humans, Pi is translo- cated into cells with two major secondary active transporters, i.e ., sodium-dependent phosphate transporter SLC20 (PiT) and SLC34 (NaPi-II) families, which prefer monovalent (H 2 PO 4 − ) and divalent (HPO 4 2− ) phosphates, respectively. 1 A dysfunction of human phosphate transporters causes numerous diseases, including hyperphosphatemia, vascular and brain calcification and neuropsychiatric disorders, but the molecular mechanism of these transporters remains elusive. h PiT ( h PiT1 and h PiT2) have been identified in various organs, including kidney, liver and brain. Specifically, the functional loss of h PiT2 in the brain can result in Pi accumulation, causing calcium phosphate deposition. Fig. 1 : (a) Topology of Tm PiT with 12 transmembrane helices that are divided into a transport domain with two inverted-topology repeats, N-PD001131 (TM1-3 and HP1a/b, in magenta) and C-PD001131 (TM6-8 and HP2a/b, in blue), and a scaffold domain (TM4/5, in yellow). (b) Ribbon diagram of the Tm PiT-Pi/Na complex consisting of a transport domain with N-PD001131 and C-PD001131 and a scaffold domain (in yellow). The Pi and Na ions are shown in CPK and as purple spheres, respectively. The transmembrane helices in (b) are coloured and numbered based on (a). (c) Ribbon diagram of the Tm PiT dimer. (d) F o − F c electron-density maps of Pi and Na are shown at 8σ and at 6σ, respectively. Transmembrane helices TM1, TM6, HP1a-HP1b and HP2a-HP2b (labeled) are involved in Pi and Na binding. The Pi- and Na-binding residues are shown in CPK and as purple spheres, respectively. (e) Magnified view of Pi-2Na binding pocket, showing interacting residues. (f) Magnified view of Na fore binding, showing the penta-coordination residues. [Reproduced from Ref. 2] The Sodium-Dependent Phosphate Transporter: To Reveal Insight into Human Solute Carrier SLC20 Dysfunctions of human phosphate transporters cause numerous diseases, but the molecular mechanism of these transporters remains elusive. The structure and function of the phosphate transporter from bacterium Thermotoga maritima in a complex with phosphate and sodium pro- vide a framework to understand PiT dysfunction and for future structure-based drug design.