Chinese scientists have revealed the mechanism of human phosphate efflux protein operation. Recently, the Chinese Academy of Sciences Institute of Physics researcher Jiang Daohua team's research results paper published in the international academic journal “Nature” magazine, the research team using cryo-electron microscopy single-particle technology and phosphate efflux functional system, the phosphate efflux protein XPR1 structure and function of the analysis, elucidated the XPR1 phosphate transport and regulatory mechanisms.
Phosphorus is the sixth most abundant macronutrient in the human body, and each adult contains about 1 kilogram of phosphorus. The Han Dynasty writer Wang Yi wrote in “Nine Thoughts - Lamenting the Years” that “God's light blazes, and ghostly flames flicker”, in which the “ghostly flames” are caused by the spontaneous combustion of phosphine produced during the degradation of corpses. 1669, the German chemist Hennig Brand was searching for the “Philosopher's Stone”, which is the most important element in the human body. In 1669, the German chemist Hennig Brand in the search for the “Philosopher's Stone” in the process, from 50 barrels of human urine accidentally obtained a kind of ash like material, can emit blue-green flame.
And modern research has shown that phosphorus is involved in almost all physiological processes in living organisms: phosphate is a major component of bones and teeth; phosphorus is involved in acid-base balance; and proteins regulate cellular metabolism by using phosphorylation/dephosphorylation as a signal.
More importantly, the human body has a system that regulates phosphate homeostasis and maintains the body's phosphate balance by controlling phosphate uptake and efflux. Among them, XPR1 is the only known phosphate efflux protein in mammals.
This time, what Daohua Jiang's team revealed is the mechanism of phosphate excretion by XPR1.
According to Daohua Jiang, adults obtain about 1,000 milligrams of phosphate from food every day, of which about 700 milligrams are absorbed by the body in the digestive and urinary systems, and the remaining phosphate is excreted in the urine and feces. Of the absorbed phosphate, 85% is stored in the body's bones and teeth, 14% enters the intracellular fluid, which maintains intracellular phosphate homeostasis, and about 1% enters the serum, which maintains phosphate homeostasis among the body's tissues.
Despite this importance of phosphate in the human body, the accumulation of excess phosphate can lead to many adverse consequences, including tumorigenesis, depression, and neuronal disorders. Therefore, it is especially important to get excess phosphate out of the cell.
However, how does protein XPR1 save the day on the cellular level and save phosphorus-imbalanced cells from “fire”? This has long been an unsolved mystery.
XPR1 first appeared in the field of vision of scientists as a cell surface receptor for retroviruses. People have since discovered that this small protein is actually multi-tasking.
Jiang Daohua told reporters that XPR1 contains a transmembrane structural domain, but also has a universal in animals, plants and microorganisms in the “versatile” protein SPX structural domain. This “match” protein as the inositol polyphosphate receptors, can feel the cell due to phosphate excess and issued “SOS”.
From the exocytosis of phosphate, to sensing the “SOS” signal, and finally saving the cells from “phosphorus”, what exactly did XPR1 do? In order to find out the truth, the research team analyzed the high-resolution structures of XPR1 in three different conformations: closed, open, and bound to inositol-6 phosphate.
Based on the structural and functional results, the researchers found that there are three sites in XPR1 formed by positively charged amino acids that bind phosphates by positive and negative attraction; when these phosphates are bound to XPR1, it induces a conformational change in XPR1, forming a channel through the cell membrane that allows phosphate ions to flow out of the cell.
XPR1 protein is very “smart”, in order to avoid excessive phosphate ion efflux leading to nutrient loss, it will utilize a flexible loop at its end to control the size of the channel opening. The SPX domain regulates the flux of phosphate ions out of XPR1 by sensing the concentration of phosphatidylinositol in the cell.
The study reveals that XPR1 is structurally similar to transporter proteins but adopts a novel channel-like gating mechanism for exocytosis of phosphate, which is significantly different from the alternately open transporter mechanism employed by the vast majority of transporter proteins.
“These findings are crucial for the study of phosphate homeostasis in the human body.” Despite the stage-by-stage progress made, some key issues still need to be explored in further research, and the team will continue to tackle the problem in this area in the future, said Jiang Daohua.
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