Naslov
Structural insights into disease-associated human prion protein mutants by NMR

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

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

Izvornik
Magnetic Moments in Central Europe 2015 Book of Abstracts / Kosiński, Krzysztof ; Urbańczyk, Mateusz ; Żerko, Szymon - Varšava : Nobell Congressing sp. z o.o., 2015, 50-50

Skup
Magnetic Moments in Central Europe 2015

Mjesto i datum
Krynica-Zdrój, Poljska, 25.02.2015. - 01.03.2015

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
prion protrein; mutants; NMR

Sažetak
Prion diseases are fatal neurodegenerative disorders which can be of sporadic, genetic and infectious origin. In genetic forms of prion diseases, misfolding of cellular prion protein, PrPC, into its pathological form, PrPSc, is caused by mutations in the human prion protein gene. Understanding of the earliest stages of the conformational changes leading to spontaneous generation of prions in genetic forms of prion diseases may benefit from detailed structural characterization of various human (Hu) PrP variants. NMR spectroscopy is a powerful tool for providing information on three-dimensional (3D) structural features at the atomic level. Therefore, we undertook solution-state NMR studies of HuPrPs with pathological Q212P and V210I mutations linked to Gerstmann-Sträussler-Scheinker (GSS) syndrome and genetic Creutzfeldt–Jakob disease (CJD), respectively and of HuPrP carrying naturally occurring E219K polymorphism considered to protect against sporadic CJD (sCJD). Nearly complete backbone and side-chain assignments along with a high number of NOE distance restraints enabled high-resolution structure determination of HuPrP variants. None of the mutation affects the overall fold of HuPrP which highly resembles that of the WT protein consisting of unstructured N-terminal tail and a globular C-terminal domain. However, pathological Q212P and V210I mutations introduce several local structural differences in comparison to the WT HuPrP. Variations are mostly clustered at the α2-α3 interhelical interface and in the β2-α2 loop region leading to higher exposure of hydrophobic residues to solvent what may facilitate intermolecular interactions involved in spontaneous generation of prions. Notably, hydrophobic interactions in the β2-α2 loop region are not interrupted in HuPrP with protective E219K polymorphism. The NMR structures of HuPrP variants provide new insights into the possible key structural determinants underlying conversion of PrPC to PrPSc. In addition, we analyzed the effect of pH on the structural features 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 may occur under acidic pH conditions in endosomal compartments.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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