Phosphate Homeostatsis

Inorganic phosphate (Pi) is one of the most essential nutrients for the maintenance of life. Pi is required for building cell membranes, DNA and RNA molecules, energy metabolism, signal transduction, and pH buffering. Pi transporters, including the SLC20 and SLC34 sodium-dependent Pi importers, the XPR1 Pi exporter, and the mitochondria Pi carrier, SLC25A3, are major modulators of intracellular Pi concentrations. Uniquely, XPR1 senses and responds to Pi levels by binding to inositol pyrophosphate (InsP8), which also connects its activity to inositol polyphosphate signaling pathways within the cell. Disorders of Pi homeostasis leading to hypo- and hyperphosphatemia are common with a range of clinical presentations. This work has significant implications for understanding basic biological processes in healthy and disease states and establishing a foundation from which to advance the treatment of lung and neurodegenerative disorders linked to calcium phosphate deposits, as well as cancer.

An initial focus has been SLC53A1, also known as xenotropic and polytropic retrovirus receptor 1 (XPR1). Inactivating mutations of XPR1 lead to brain calcifications, causing neurological symptoms that include migraine, movement disorders, psychosis, and dementia. Through the determination of cryo-EM structures of dimeric human XPR1 and its functional characterization, we have defined the substrate translocation pathway and delineated how InsP8 binding initiates the transport cycle.