ABSTRACT
Intermolecular interaction between hPrP and αS was investigated using high-speed atomic force microscopy, dynamic light scattering, and nuclear magnetic resonance. We found that hPrP spontaneously gathered and naturally formed oligomers. Upon addition of monomer αS with a disordered conformation, poly-dispersive property of hPrP was lost, and hetero-dimer formation started quite coherently, and further oligomerization was not observed. Solution structure of hPrP-αS dimer was firstly characterized using hetero-nuclear NMR spectroscopy. In this hetero-dimeric complex, C-terminal helical region of hPrP was in the molten-globule like state, while specific sites including hot spot and C-terminal region of αS selectively interacted with hPrP. Thus αS may suppress amyloidogenesis of hPrP by trapping the hPrP intermediate by the formation of a stable hetero-dimer with hPrP.
Abbreviations: hPrP, human prion protein of amino acid residues of 23-231; PrPC, cellular form of prion protein; PrPSc, scrapie form of prion protein, HS-AFM; high speed atomic force microscopy; αS, α-synuclein; DLS, dynamic light scattering
Acknowledgments
This work was supported by grants from the Ministry of Health, Labour, and Welfare of Japan [Research on Measures for Intractable Diseases (Prion Disease and Slow Virus Infections, and Development of Low Molecular Weight Medical Chaperone Therapeutics for Prion Diseases #17ek0109075h)] and the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Grants-in Aid for Scientific Research #19H03476). We also thank M. Kobayashi for providing technical help.
Disclosure statement
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Supplementary material
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