Human XPR1 structures reveal phosphate export mechanism

• 成果类型: Article
• 署名作者: Yan, Rui; Chen, Huiwen; Liu, Chuanyu; Zhao, Jun; Wu, Di; Jiang, Juquan; Gong, Jianke; Jiang, Daohua
• 署名单位: Chinese Academy of Sciences; Institute of Physics, CAS; Huazhong University of Science & Technology; Northeast Agricultural University - China; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Peking University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6126
• DOI: 10.1038/s41586-024-07852-9
• 发表日期: 2024-09-26
• 关键词: cell-surface receptor; leukemia viruses; cryo-em; homeostasis; domain; gene; expression; mutations; channel

摘要

Inorganic phosphate (Pi) is a fundamental macronutrient for all living organisms, the homeostasis of which is critical for numerous biological activities(1-3). As the only known human Pi exporter to date, XPR1 has an indispensable role in cellular Pi homeostasis(4,5). Dysfunction of XPR1 is associated with neurodegenerative disease(6-8). However, the mechanisms underpinning XPR1-mediated Pi efflux and regulation by the intracellular inositol polyphosphate (InsPP) sensor SPX domain remain poorly understood. Here we present cryo-electron microscopy structures of human XPR1 in Pi-bound closed, open and InsP(6)-bound forms, revealing the structural basis for XPR1 gating and regulation by InsPPs. XPR1 consists of an N-terminal SPX domain, a dimer-formation core domain and a Pi transport domain. Within the transport domain, three basic clusters are responsible for Pi binding and transport, and a conserved W573 acts as a molecular switch for gating. In addition, the SPX domain binds to InsP(6) and facilitates Pi efflux by liberating the C-terminal loop that limits Pi entry. This study provides a conceptual framework for the mechanistic understanding of Pi homeostasis by XPR1 homologues in fungi, plants and animals.