New insights into structural determinants of prion protein folding and stability.
Prions are the etiological agent of fatal neurodegenerative diseases called prion diseases or transmissible spongiform encephalopathies. These maladies can be sporadic, genetic or infectious disorders. Prions are due to post-translational modifications of the cellular prion protein leading to the formation of a β-sheet enriched conformer with altered biochemical properties. The molecular events causing prion formation in sporadic prion diseases are still elusive. Recently, we published a research elucidating the contribution of major structural determinants and environmental factors in prion protein folding and stability. Our study highlighted the crucial role of octarepeats in stabilizing prion protein; the presence of a highly enthalpically stable intermediate state in prion-susceptible species; and the role of disulfide bridge in preserving native fold thus avoiding the misfolding to a β-sheet enriched isoform. Taking advantage from these findings, in this work we present new insights into structural determinants of prion protein folding and stability.
a Laboratory of Prion Biology, Department of Neuroscience; Scuola Internazionale Superiore di Studi Avanzati (SISSA) , Trieste , Italy.
Federico
F
Benetti
Giuseppe
G
Legname
D000818:Animals; D002417:Cattle; D004220:Disulfides / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D017510:Protein Folding; D055550:Protein Stability; D017434:Protein Structure, Tertiary
D004220:Disulfides; D011328:Prions
ADAM family, A Disintegrin And Metalloproteinase family; CJD, Creutzfeldt-Jakob disease; FFI, fatal familial insomnia; GPI, glycosylphosphatidylinositol; GSS, Gerstmann-Sträussler-Scheinker syndrome; N-terminal domain; NMDA receptor, N-methyl-D-aspartate receptor; OR, octarepeats; PrPC, cellular prion protein; PrPSc, prion; TSE, transmissible spongiform encephalopathies; disulfide bridge; folding; globular domain; intermediate state; octarepeat; prion protein; stability