Transport and InsP8 activation mechanisms of the human inorganic phosphate exporter XPR1

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Summary Inorganic phosphate (Pi) has essential metabolic and structural roles in living organisms. The Pi exporter, XPR1/SLC53A1, is critical for maintaining cellular Pi homeostasis. When intercellular Pi is high, cells synthesize inositol pyrophosphate (1,5-InsP 8 ) – a signaling molecule that is required for XPR1 function. Inactivating mutations of XPR1 lead to brain calcifications causing neurological symptoms that include migraine, movements disorders, psychosis, and dementia. Distinct cryo-electron microscopy structures of dimeric XPR1 and functional characterization define the substrate translocation pathway and delineate how binding of InsP 8 initiates the transport cycle. InsP 8 binding rigidifies the intracellular SPX domains with InsP 8 acting as a bridge between dimers and the SPX and transmembrane domains. When locked in this state, the C-terminal tail is sequestered revealing the entrance to the transport pathway, thus explaining the obligate roles of the SPX domain and InsP 8 . Together, these findings advance our understanding of XPR1 transport activity and expand opportunities for rationalizing disease mechanisms and therapeutic intervention.

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