Naslov
Solution NMR structures of disease-linked human prion protein mutants

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

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

Izvornik
The Second BIO-NMR Annual User Meeting : Breakthroughs in NMR of Structural Biology / Vodiškar, Mateja ; Plavec, Janez - Ljubljana : Slovenian NMR Cenre, National Institute of Chemistry, 2012, 77-77

ISBN
978-961-6104-18-0

Skup
The Second Bio-NMR Annual User Meeting

Mjesto i datum
Portorož, Slovenija, 08.05.2012. - 11.05.2012

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Prions ; Mutants ; NMR structure

Sažetak
Prion diseases or transmissible spongiform encephalopathies (TSEs) are a group of rare neuropathies characterized by a spongiform neurodegeneration of the central nervous system caused by prions. These disorders include Creutzfeldt–Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome, Fatal Familial Insomnia and kuru in humans, bovine spongiform encephalopathy in cattle, scrapie in sheep and goats, and chronic wasting disease in elk, deer and moose. 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 α-helix motives are replaced by β-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. In our recent studies, we have determined the NMR solution-state structures of the truncated recombinant human (Hu) PrPs carrying the pathological Q212P (90-231, M129)1 and V210I (90-231, M129)2 mutations linked to GSS and genetic CJD, respectively. In order to determine high-resolution structures triple resonance (1H, 13C and 15N) NMR experiments were performed using 800 MHz NMR spectrometer. The determined structures of both mutants consist of unstructured N-terminal part (residues 90-124) and well-defined C-terminal domain (residues 125-228). The C-terminal part contains three -helices (residues 144-156, 173-193 and 200-230) and a short, antiparallel -sheet (residues 129-130 and 162-163). 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 α2-α3 inter-helical interface and in the β2-α2 loop region. The alteration of conformation of the β2–α2 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 development of antiprion drugs.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA