Structural basis for inositol pyrophosphate gating of the phosphate channel XPR1.

Autor: Lu Y; Institute of Precision Medicine, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.; Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China., Yue CX; School of Basic Medicine and Clinical Pharmacy and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China., Zhang L; Institute of Precision Medicine, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.; Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Yao D; Institute of Aging & Tissue Regeneration, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China., Xia Y; Institute of Precision Medicine, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China., Zhang Q; Institute of Precision Medicine, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.; Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China., Zhang X; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China., Li S; Institute of Precision Medicine, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China., Shen Y; Institute of Precision Medicine, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China., Cao M; Institute of Precision Medicine, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China., Guo CR; School of Basic Medicine and Clinical Pharmacy and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China., Qin A; Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.; Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China., Zhao J; Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.; Shanghai Frontiers Science Center of Degeneration and Regeneration in Skeletal System, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China., Zhou L; Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China., Yu Y; School of Basic Medicine and Clinical Pharmacy and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China., Cao Y; Institute of Precision Medicine, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.; Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2024 Nov 15; Vol. 386 (6723), pp. eadp3252. Date of Electronic Publication: 2024 Nov 15.
DOI: 10.1126/science.adp3252
Abstrakt: Precise regulation of intracellular phosphate (Pi) is critical for cellular function, with xenotropic and polytropic retrovirus receptor 1 (XPR1) serving as the sole Pi exporter in humans. The mechanism of Pi efflux, activated by inositol pyrophosphates (PP-IPs), has remained unclear. This study presents cryo-electron microscopy structures of XPR1 in multiple conformations, revealing a transmembrane pathway for Pi export and a dual-binding activation pattern for PP-IPs. A canonical binding site is located at the dimeric interface of Syg1/Pho81/XPR1 (SPX) domains, and a second site, biased toward PP-IPs, is found between the transmembrane and SPX domains. By integrating structural studies with electrophysiological analyses, we characterized XPR1 as an inositol phosphates (IPs)/PP-IPs-activated phosphate channel. The interplay among its transmembrane domains, SPX domains, and IPs/PP-IPs orchestrates the conformational transition between its closed and open states.
Databáze: MEDLINE
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