Chinese scientists analyze the frozen electroscope structure of prion protein amyloid fibers

of protein misfolding and disease has always been one of the hot topics in the field of life science.
23 p.m. Beijing time on June 8, 2020, Nature Structural and Molecular Biology published the latest research results from the Wuhan University team and the China
Shanghai Organic Institute Cross Center team online in the form of Article.
researchers analyzed the high-resolution frozen electroscopic structure of full-length prion protein fibers at the atomic level for the first time, revealing the molecular mechanism of the shift from cell-type prion protein to pathological prion protein structure, and laying the foundation for the development of new prion disease treatment drugs based on prion protein fiber structure.
Liang Yi, Professor of the School of Life Sciences of Wuhan University, and
Liu Cong, Professor of the Shanghai Organic Institute Crossing Center, are co-authors of the paper, Wang Liqiang, Ph.D. student of the School of Life Sciences of Wuhan University, and Zhao Wei, Ph.D. student of the Shanghai Organic Institute of China
, are co-authors of the paper, and Yin Ping, Professor Yin Ping of the School of Life Sciences of Huazhong Agricultural University, and Yuan Wei, Ph.D. student of the School of Life Sciences of Wuhan University, are among the co-authors of the paper.
research was supported by the National Natural Science Foundation of China and the Ministry of Science and Technology.The frozen electroscopic structure
infectious spongior encephalopathy (TSE) or prion disease is a deadly neurodegenerative disease caused by the misfolding of prion protein (PrP) in the body, affecting a variety of mammals, including humans.
Prion protein is encoded by the host gene PRNP, and the properly folded protein is not only non-pathogenic and infectious, but also has important physiological functions;
the 1997 Nobel Prize in Physiology or Medicine, S. Professor Prusiner was the first to describe the prion virus, the protein infection factor.
Among humans and other mammals, common prion diseases include mad cow disease (BSE), scrapie and human CJD, fatal family insomnia (FFI) and Gerstman's syndrome (GSS), as well as chronic consumption disease (CWD) in deer.
pathological features of Preon disease are the transformation of PrP from cytoplin (PrP
) to pathological prion protein (PrP
), and the amyloid fibers of PrP
and PrP can be used as templates to induce a structural transformation of PrP
.
" Cryo-EM technology is revolutionising protein misfolding and disease, and analyzing the high-resolution structure of PrP
and full-length PrP fibers will be a huge boost to understanding the pathogenesis of prion disease. The paper points out.
But so far, due to the insoluble and heterogeneous nature of PrP
and PrP fibers, there is still no high-resolution PreP
and full-length PrP fiber structure, greatly limiting the development of PrP fiber-based prion disease treatment drugs.
Liang Yi, in order to explain the structural basis of the transition from cell-type prion protein to pathological prion protein, in this study, the researchers prepared a highly equal full-length human prion amyloid fiber, and used cryoentherapy combined with 3D reconstruction technology to analyze the full length at the atomic level The high-resolution structure of prion protein fiber (2.70 s) was found to consist of two primary fibers wound in a left-handed spiral, with a fiber width of 25 nm, a fiber core diameter of 14 nm and a half helix cycle of 78.5 nm.
further studies have found that the core of prP fiber consists mainly of 170-229 at its C end and consists of six β-folding structures (from beta 1 to beta 6).
in the PrP aggregation process, two primary fibers interact through the salt bridge formed between Lys194 and Glu196, forming a hydrophobic cavity at the interface of their interaction.
The researchers explored the pathological significance of such a novel structure and found that the three key amino acid residues Lys194, Glu196, and Glu211 that formed the salt bridge in the PrP fiber structure were all pathological mutation site associated with the prion disease.Based on the above conclusions
, the researchers suggest that two α-helixes at the PrP
C end were transformed into six
β-folding structures of PrP fibers, and that the two sulfur bonds between Cys179 and Cys214 acted as stable powder fibers during the PrP misfolding process.
The study reveals for the first time the mechanism of PrP's transformation from PrP
to PrP
structure at the atomic level, reveals that different pathological mutants may play different roles in regulating the transformation of prion protein composition, and makes it possible to develop new preon disease therapy drugs based on PrP fiber structure, laying the foundation for in-depth study of PrP
structure and pathogenic function. (Source: Science Network)
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