Naslov
NMR insights into the effects of disease-related mutations on human prion protein structure

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

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

Izvornik
Programme & Book of Abstract, Pharma NMR Conference, Application of NMR Spectroscopy in Pharmaceutical Industry / Novak, Predrag ; Tomišić, Vladislav ; Bregović, Nikola - Zagreb : International Association of Physical Chemists (IAPC), 2015, 21-21

Skup
Pharma NMR Conference, Application of NMR Spectroscopy in Pharmaceutical Industry

Mjesto i datum
Rovinj, Hrvatska, 23.09.2015. - 25.09.2015

Vrsta sudjelovanja
Poster

Vrsta recenzije
Domaća recenzija

Ključne riječi
Prion protein; Mutations; NMR spectroscopy

Sažetak
Prion diseases are a rare group of fatal neurodegenerative disorders affecting humans and animals. The key event in prion diseases is the conformational conversion of the normal, cellular prion protein, PrPC, into a disease-related form known as prion or PrPSc. Approximately 10-15% of prion diseases in humans are caused by mutations in the PrP gene (PRNP). Structural characterization of different human (Hu) PrP variants may be helpful for better understanding of the earliest stages of the conformational changes leading to spontaneous generation of prions in inherited forms of prion diseases. In our recent NMR studies we examined the effects of several disease-related mutations on HuPrP structure. We determined solution-state NMR structures of the truncated recombinant HuPrPs (residues 90-231) carrying pathological Q212P and V210I mutations linked to Gerstmann-Straussler-Schenker (GSS) syndrome and familial Creutzfeldt-Jakob disease (CJD), respectively, and of HuPrP with naturally occurring E219K polymorphism considered to protect against sporadic CJD (sCJD). NMR structures of HuPrP(Q212P), HuPrP(V210I) and HuPrP(E219K) proteins share similar global architecture with the WT HuPrP comprising unstructured N-terminal tail and a globular C-terminal domain. Detailed analysis revealed that pathological Q212P and V210I mutations introduce subtle local structural changes with respect to the WT HuPrP. These include perturbation of hydrophobic contacts at the α2-α3 inter-helical interface, altered conformation of the β2-α2 loop along with loosening of tertiary contacts between the loop and the C-terminal end of helix α3 leading to higher exposure of hydrophobic residues to solvent. Notably, the structure of HuPrP(E219K) does not point to interruption of hydrophobic interactions in the β2-α2 loop region. Our structural findings on disease-related HuPrP mutants offer new clues about the earliest events of the pathogenic conversion process. In addition, we examined the effect of pH on the structure of HuPrP(V210I). Comparison of NMR structures of HuPrP(V210I) at pH 5.5 and 7.2 revealed that the tertiary contacts are less perturbed at neutral pH conditions suggesting that spontaneous formation of prions probably occurs under acidic pH conditions in endosomal compartments.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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