Naslov
A single point mutation, a way to prion disease?

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

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

Izvornik
Abstract Book MMCE 2013 / Konrat, Robert ; Kontaxis, Georg - Beč : Universität Wien, 2013, 11-11

Skup
Magnetic Moments in Central Europe

Mjesto i datum
Semmering, Austrija, 27.02.2013. - 03.03.2013

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Prion protein; Mutants; NMR spectroscopy; pH

Sažetak
Prion diseases or Transmissible Spongiform Encephalopathies (TSE) are a group of fatal neurodegenerative illnesses affecting humans and animals. They are classified into sporadic, genetic and infectious forms. Genetic prion diseases are caused by mutations in the human prion protein gene and include Gerstmann-Straussler-Scheinker (GSS) syndrome, Fatal Familial Insomnia and genetic Creutzfeldt-Jakob disease (CJD). Approximately 10-15% of all TSE cases in humans are associated with mutations. The development of TSEs is associated with the conversion of the cellular prion protein (PrPC) into a misfolded, pathogenic isoform (PrPSc). Our recent NMR studies were focused on structural characterization of different truncated recombinant human (Hu) PrPs carrying the pathological Q212P (90-231, M129) and V210I(90-231, M129) mutations, and protective E219K (90-231, M129) polymorphism. While Q212P mutation is linked to GSS, the V210I mutation is linked to genetic CJD. The naturally occurring E219K polymorphism in the HuPrP is considered to protect against sCJD. We have demonstrated that the determined structures of variants consist of unstructured N-terminal part (residues 90-124) and well defined C-terminal domain (residues 125-228). Analysis and comparison with the structure of the WT HuPrP revealed that although structures share similar global fold, mutations introduces several local structural differences. The observed differences are mostly clustered at the alpha2-alpha3 inter-helical interface and in the beta2-alpha2 loop region. The determined NMR structures offer new insights on the earliest events of the pathogenic conversion process and could be used for the development of antiprion drugs. More recently we have determined solution state structures of V210I (90-231, M129) pathogenic mutation at two different conditions with pH 5.5 and 7.2. The detailed comparison of three-dimensional structures of HuPrP(V210I) at two different pH values revealed that interactions among secondary structure elements have a higher degree of structural ordering under neutral pH conditions, thus implying that spontaneous misfolding of PrPC may occur under acidic-pH conditions in endosomal compartments.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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