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2024

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08

Jiang Daohua's team reported the molecular mechanism of the transport and regulation of the phosphate efflux protein XPR1!

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Inorganic phosphate (Pi) is an essential macronutrient for all living organisms, and its homeostasis is essential for many biological activities. As the only known human Pi export gene to date, XPR1 plays an integral role in cellular Pi homeostasis.XPR1 dysfunction is associated with neurodegenerative diseases.However, supportXPR1Mediated Pi efflux and intracellular inositol polyphosphate (InsPP) sensorSPXThe mechanisms of domain regulation are still poorly understood.

On August 21, 2024, Jiang Daohua's team from the Institute of Physics of the Chinese Academy of SciencesNaturePublished online entitled"Human XPR1 structures reveal phosphate export mechanism"'s research paper,The studydemonstrated the human XPR1 protein inPiCombined Closed, Open and InsP6The cryo-electron microscope structure under the binding form revealed that the XPR1 protein wasInsPPsStructural basis of gating and regulation.

XPR1 consists of an N-terminal SPX domain, a dimer-forming nuclear domain, and a Pi transport domain. Within the transport domain, three basic clusters are responsible for Pi binding and transport, and one conserved W573 acts as a gated molecular switch. In addition, the SPX domain and the InsP6binding, promotes Pi spillover by releasing a C- terminal loop that restricts Pi entry.This study provides a conceptual framework for understanding the mechanism of XPR1 homologs on Pi homeostasis in fungi, plants and animals.

Phosphorus is an essential element in all areas of life, involved in bone and tooth growth, lipid and nucleic acid biogenesis, metabolism of high-energy organic compounds, and protein signaling.Cellular Pi levels are tightly regulated to match the biosynthetic demand for Pi and to avoid excessively high cytoplasmic Pi levels; dysregulation of Pi homeostasis leads to pathological consequences.In mammals, cells take up Pi from the extracellular space through the PiT (also known as SLC20A) and NPT2 (also known as SLC34A) transporters. In contrast, as the only known mammalian Pi exporter to date, the allo-and multidirectional retroviral receptor 1 (XPR1;SLC53A1 coding) mediates Pi efflux in response to elevated intracellular Pi levels, and thus plays a critical role in maintaining cellular Pi homeostasis. In mice, deletion of the gene encoding XPR1, and loss-of-function mutations in XPR1 have been linked to human neurological disorders primary familial cerebral calcification (PFBC) and renal Fanconi syndrome, is fatal.

In plants, phosphate 1 (PHO1) transports π from the root to the stem, and plays an indispensable role in plant π homeostasis and signal transmission.In yeast, SYG1 is a homolog of XPR1 and PHO1 and is considered a Pi exporter. The sequence homology of these three proteins is about 25%, and has the conservation of the N-terminal SPX (SYG1, PHO81, XPR1) domain and the subsequent transmembrane domain (TMD)topology. TMD consists of 10 transmembrane helices, of which 6 transmembrane helices at the C- terminus are named EXS (Erd1, XPR1, SYG1) domain 20, which are essential for Pi transport. SPX domain-containing proteins are widely distributed in fungi, plants andmetazoanand is considered to be an inositol polyphosphate (InsPP) sensor that monitors intracellular InsPP and regulates cellular Pi levels through Pi transporters or Pi-dependent transcription factors.Although the structure of the conserved SPX domain has been revealed, the structure of XPR1 homologs and how the SPX domain communicates with TMDs remain largely unknown.

XPR1 is widely expressed in human tissues and was initially identified as an allo-and polytropism mouseLeukemia virusof the receptor. Studies have shown that XPR1 mediates Pi spillover.Although XPR1 maintains Pi export activity in the absence of the SPX domain, its function can be enhanced by the SPX domain, which senses InsPPs within cells, including 1,5-InsP8.The increase in intracellular Pi levels leads to the accumulation of InsPPs, which in turn bind to the SPX domain and promote Pi spillover through XPR1 to balance cellular Pi levels. However, the underlying mechanism of how XPR1 recognizes and transports Pi and how this process is regulated by the SPX domain remains unclear.
In this study, the authors determined the binding of human XPR1 protein to Pi and hexylphosphoinositide (InsP6) Cryo-electron microscopy (cryo-EM) structures in three different functional states, showing the structural characteristics and Pi export mechanism of XPR1-like proteins.Combined with the functional mutagenesis results, this study elucidates Pi binding, gating, InsPP sensing, and the coupling between InsPP sensing and Pi output in XPR1, which are essential for human Pi homeostasis.
Jiang Daohua, a distinguished researcher at the Institute of Physics, Chinese Academy of Sciences, is the only corresponding author of this study. Yan Rui, a doctoral student jointly trained by Huazhong University of Science and Technology and the Institute of Physics, Chen Huiwen, a postdoctoral student of the Institute of Physics, Liu Chuanyu, a doctoral student of the Institute of Physics, and Zhao Jun of the Institute of Modern Agriculture of Peking University are the co-first authors of this article. In addition, Wu Di, a doctoral student in the Institute of Physics, also provided assistance for this study.

This study was funded by the National Foundation of China and the Chinese Academy of Sciences. Cryo-electron microscopy data collection was supported by the Cryo-electron Microscopy Center of the Institute of Physics, Chinese Academy of Sciences, the Soft Matter Public Instrument Platform and the Biological Microstructure Research Platform of the Institute of Modern Agriculture, Peking University.

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