Human XPR1 structures reveal phosphate export mechanism.

Autor: Yan R; Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China.; College of Life Science and Technology, Key Laboratory of Molecular Biophysics of MOE, Huazhong University of Science and Technology, Wuhan, China., Chen H; Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China.; Department of Microbiology and Biotechnology, College of Life Sciences, Northeast Agricultural University, Xiangfang District, Harbin, China., Liu C; Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China.; University of Chinese Academy of Sciences, Beijing, China., Zhao J; Peking University Institute of Advanced Agricultural Sciences, Shandong Laboratory of Advanced Agricultural Sciences at Weifang, Weifang, China., Wu D; Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China.; University of Chinese Academy of Sciences, Beijing, China., Jiang J; Department of Microbiology and Biotechnology, College of Life Sciences, Northeast Agricultural University, Xiangfang District, Harbin, China., Gong J; College of Life Science and Technology, Key Laboratory of Molecular Biophysics of MOE, Huazhong University of Science and Technology, Wuhan, China., Jiang D; Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China. jiangdh@iphy.ac.cn.; University of Chinese Academy of Sciences, Beijing, China. jiangdh@iphy.ac.cn.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Sep; Vol. 633 (8031), pp. 960-967. Date of Electronic Publication: 2024 Aug 21.
DOI: 10.1038/s41586-024-07852-9
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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