Naslov
NMR structural insights into effects of point mutations in Human genome on prion protein

Autori
Ilc, Gregor ; Biljan, Ivana ; Giachin, Gabriele ; Zhukov, Igor ; Legname, Giuseppe ; Plavec, Janez

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
3rd Annual East-NMR User Meeting / Vodiškar, Mateja ; Podbevšek, Peter ; Plavec, Janez ; Lenarčič Živković, Martina - Ljubljana : Slovenian NMR Cenre, National Institute of Chemistry, 2012, 62-62

ISBN
978-961-6104-21-0

Skup
3rd Annual East-NMR User Meeting

Mjesto i datum
Laško, Slovenija, 13.11.2012. - 16.11.2012

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Prions ; Mutants ; NMR structure

Sažetak
Transmissible spongiform encephalopathies (TSEs), or prion diseases, are invariably fatal neurodegenerative disorders affecting humans and animals. Human prion diseases include Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), Gerstmann-Sträussler-Scheinker (GSS) syndrome, and kuru, whereas the most common prion diseases in animals are scrapie in sheep, bovine spongiform encephalopathy, and chronic wasting disease in cervids. Prions are thought to consist solely of a misfolded isoform (PrPSc) of the normal, host-encoded cellular protein (PrPC), whose function is still unknown. Human (Hu) PrPC is a 209 residues long glycoprotein, tethered to the outer leaflet of the plasma membrane by a glycosylphosphatidylinositol (GPI) anchoring and its primary structure is highly conserved among mammals. According to the „protein-only hypothesis”, during the course of prion diseases, PrPC is converted into the abnormal form by a conversion process whereby most alpha-helix motives are replaced by beta-sheet secondary structures. One of the strongest arguments supporting the „protein-only hypothesis” is the link between inherited prion diseases and mutations in the PRNP gene. Approximately 10-15 % of TSEs are associated with mutations. In our recent works, we have determined the NMR solution-state structures of the truncated recombinant human (Hu) PrPs carrying the pathological Q212P (90-231, M129) and V210I (90-231, M129) mutation. While Q212P mutation is linked Gerstmann-Sträussler-Scheinker syndrome (GSS) the V210I mutation is linked to genetic Creutzfeldt-Jakob disease (CJD). In order to determine high-resolution structures triple resonance (1H, 13C and 15N) NMR experiments were performed by 800 MHz NMR spectrometer. Detailed analysis and comparison with the structure of the WT Hu-PrP revealed that although structures share similar global fold, mutations introduces some local structural differences. The observed variations are mostly clustered at the alpha2-alpha3 inter-helical interface and in the beta2-alpha2 loop region. The alteration of conformation of the beta2–alpha2 loop region and the subsequent changes in hydrophobic cluster may facilitate intermolecular interactions between PrPs. The high-resolution NMR structures offer new clues on the earliest events of the pathogenic conversion process and could be used for the the development of antiprion drugs.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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