Naslov
Insights into local structural variations in human prion proteins with inherited mutations by NMR

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

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

Izvornik
6th SISSA/ELETTRA PRION Research WORKSHOP / - Trst, 2013, 16-16

Skup
6th SISSA/ELETTRA PRION Research WORKSHOP

Mjesto i datum
Trst, Italija, 10.01.2013. - 11.01.2013

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Prions; NMR structure; Mutants; pH

Sažetak
Prion diseases are fatal neurodegenerative disorders caused by an aberrant accumulation of the infectious scrapie isoform (PrPSc). Understanding of the mechanisms by which cellular prion protein (PrPC) misfolds and leads to disease can benefit from detailed analysis of 3D structures. Our recent NMR studies have focused on structural characterization of different human PrPC variants that are linked to genetic prion diseases. We have demonstrated that structures of Q212P (Ilc et al., 2010), V210I (Biljan et al., 2011) and E219K (Biljan et al., 2012a) mutants exhibit unique structural features that are caused by a single amino acid substitution. Interestingly, the naturally occurring E219K polymorphism in the human prion protein is considered to protect against sporadic Creutzfeldt–Jakob disease. In all studies, 13C, 15N-double labeled mutants were prepared and exhibited favorable cross-peak dispersion in 1H-15N HSQC spectra thus enabling complete spectral assignment and acquisition of a large number of NOE based distance restraints. In general, the structure of the mutant proteins consist of a disordered N-terminal tail (residues 90–124) and a well-structured C-terminal segment (residues 125–231) containing three α-helices and two short antiparallel β-strands. More recently, we have characterized HuPrP(90-231) carrying V210I mutation under two different conditions with pH 5.5 and 7.2 (Biljan et al., 2012b). While nearly complete assignment was obtained for V210I mutant at pH 5.5, amide protons are involved in fast exchange with solvent at pH 7.2 which renders observation of some amino acids residues from unstructured N-terminal region. Significant pH-related local structural differences were observed in the α2−α3 interhelical region, at the interface of the β1−α1 loop, in helices α1 and α3, and in the β2−α2 loop region. The detailed analysis of interactions suggests that spontaneous misfolding of PrPC may occur under acidic-pH conditions in endosomal compartments.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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