Prion diseases are a group of neurodegenerative disorders that can arise spontaneously, through infection or through inheritance of mutations in the gene encoding the prion protein (PrP). According to the "protein-only hypothesis", the key event in the pathogenesis of prion disorders is the conversion of a cellular, highly alpha-helical PrP into a pathogenic beta -sheet enriched form, PrPSc. One of the strongest arguments supporting "protein-only hypothesis" is the linkage between inherited prion diseases and mutations in the gene coding for human PrP. However, the mechanisms by which mutations cause diseases are still not resolved. Structural studies of PrP variants carrying familial mutations could help us to understand the molecular mechanism at early stage of disease. In this study we have determined a high-resolution 3D structure of the truncated recombinant HuPrP(90-231) containing Q212P mutation associated with Gerstmann-Straussler-Scheinker (GSS) syndrome. The obtained structure reveals unique structural features in comparison to the known wild-type PrP structures with the most remarkable di erences at the C-terminal end of the protein and in the beta 2-alpha 2 loop. The C-terminal domain (residues 125-231) consists of a short anti-parallel beta-sheet and four alpha helices. This is the first known example of PrP structure where the alpha3 helix between Glu200 and Tyr226 is broken into two alpha helices. The break results in dramatic changes in hydrophobic interactions between alpha3 helix and beta2- alpha2 loop. In comparison to WT a different mutual orientation of aromatic residues in beta 2- alpha2 loop has been observed. In Q212P mutant Tyr169 is exposed to solvent and as a result the whole hydrophobic cluster is changed and shows increased exposure of hydrophobic surface of the protein to solvent. Spontaneous generation of PrPSc in inherited prion diseases might be due to the disruptions of the hydrophobic core consisting of beta 2- alpha2 loop and alpha3 helix.
NMR structure of the human prion protein Q212P mutant / Ilc, G; Giachin, G; Biljan, I; Jaremko, M; Jaremko, L; Benetti, F; Zhukov, I; Legname, Giuseppe; Plavec, J.. - (2011). (Intervento presentato al convegno Bio-NMR and EAST-NMR Annual User Meeting tenutosi a Brno, Češka nel 24.-27.01.2011).
NMR structure of the human prion protein Q212P mutant
Giachin G;Legname, Giuseppe;
2011-01-01
Abstract
Prion diseases are a group of neurodegenerative disorders that can arise spontaneously, through infection or through inheritance of mutations in the gene encoding the prion protein (PrP). According to the "protein-only hypothesis", the key event in the pathogenesis of prion disorders is the conversion of a cellular, highly alpha-helical PrP into a pathogenic beta -sheet enriched form, PrPSc. One of the strongest arguments supporting "protein-only hypothesis" is the linkage between inherited prion diseases and mutations in the gene coding for human PrP. However, the mechanisms by which mutations cause diseases are still not resolved. Structural studies of PrP variants carrying familial mutations could help us to understand the molecular mechanism at early stage of disease. In this study we have determined a high-resolution 3D structure of the truncated recombinant HuPrP(90-231) containing Q212P mutation associated with Gerstmann-Straussler-Scheinker (GSS) syndrome. The obtained structure reveals unique structural features in comparison to the known wild-type PrP structures with the most remarkable di erences at the C-terminal end of the protein and in the beta 2-alpha 2 loop. The C-terminal domain (residues 125-231) consists of a short anti-parallel beta-sheet and four alpha helices. This is the first known example of PrP structure where the alpha3 helix between Glu200 and Tyr226 is broken into two alpha helices. The break results in dramatic changes in hydrophobic interactions between alpha3 helix and beta2- alpha2 loop. In comparison to WT a different mutual orientation of aromatic residues in beta 2- alpha2 loop has been observed. In Q212P mutant Tyr169 is exposed to solvent and as a result the whole hydrophobic cluster is changed and shows increased exposure of hydrophobic surface of the protein to solvent. Spontaneous generation of PrPSc in inherited prion diseases might be due to the disruptions of the hydrophobic core consisting of beta 2- alpha2 loop and alpha3 helix.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
