The identification of XPR1 as a voltage- and phosphate-activated phosphate-permeable ion channel
Year: 2025
Type: article
Abstract: Maintaining a balance of inorganic phosphate (Pi) is vital for cellular functionality due to Pi's essential role in numerous biological processes. Proper phosphate levels are managed through Pi import and export, facilitated by specific Pi transport proteins. Although the mechanisms of Pi import have been extensively studied, the processes governing Pi export remain less understood. Xenotropic and Polytropic retrovirus Receptor 1 (XPR1) has been identified as the only known Pi export protein in mammals, playing a key role in facilitating Pi efflux from cells. Malfunctions in XPR1 are associated with human diseases, such as primary familial brain calcification and certain cancers, highlighting its critical role in maintaining Pi homeostasis. In this study, we introduce the cryogenic electron microscopy structure of human XPR1 (hXPR1), unveiling a structural arrangement distinct from that of any known ion transporter, with a topology not identified in previous computational predictions. Our structural results suggest that hXPR1 may operate as an ion channel, a hypothesis supported by patch clamp recordings revealing hXPR1's voltage- and Pi-dependent activity and large unitary conductance. Using proteoliposomal uptake assays, we demonstrate that purified and reconstituted hXPR1 catalyzes transport of Pi. Further analysis, including the structure of hXPR1 in presence of Pi, and functional effects of mutating a putative Pi binding site, leads us to propose a plausible ion permeation pathway. Together, our results provide novel perspectives on the Pi transport mechanism of XPR1 and its homologues.
Source: Nature Communications
Authors: Hongjiang Wu, Liang Sun, Tong Huo, Theodore G. Wensel, Frank T. Horrigan, Zhao Wang
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Health and Human Services, Cancer Prevention and Research Institute of Texas, University of Texas Health Science Center at Houston, National Institutes of Health, National Heart, Lung, and Blood Institute, National Eye Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases
Awards: New Capabilities for Cancer Research in the TMC CryoEM Cores, G5045715109, Investigation of the Cellular and Molecular Mechanisms of Thrombocyte Integrin Signaling, G5751507505, G5778553540, Cilium-associated structures in rod cells, Customized and Integrated Multi-Angle Light Scattering (MALS)-based Multidetection System, Cardiovascular drug target, TRPV2, Molecular Assembly of Bacterial Tripartite Multidrug Efflux Pumps
OpenAlex ID: W4410401585