Anchorless forms of prion protein - Impact of truncation on structure destabilization and prion protein conversion.
Prion diseases are a group of fatal neurodegenerative diseases caused by scrapie form of prion protein, PrPSc. Prion protein (PrP) is bound to the cell via glycophosphatidylinositol (GPI) anchor. The role of GPI anchor in PrPScreplication and propagation remains unclear. It has been shown that anchorless and truncated PrP accelerate the formation and propagation of prions in vivo and further increases the risk for transmission of prion diseases among species. To explain the role of anchorless forms of PrP in the development of prion diseases, we have prepared five C-terminal PrP truncated variants, determined their thermodynamic properties and analyzed the kinetics of conversion into amyloid fibrils. According to our results thermodynamic and kinetic properties are affected both by pH and truncation. We have shown that the shortest variant was the most destabilized and converted faster than other variants in acidic pH. Other variants converted with longer lag time of fibrillization than WT despite comparable or even decreased stability in acidic pH. Our results indicate that even the change in length for 1 amino acid residue can have a profound effect on in vitro conversion.
Department for the Production of Diagnostic Reagents and Research & R&D Service, Blood Transfusion Centre of Slovenia, Šlajmerjeva 6, SI-1000, Ljubljana, Slovenia.
Valerija
V
Kovač
Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, SI-1000, Ljubljana, Slovenia; EN-FIST Centre of Excellence, Trg Osvobodilne fronte 13, 1000, Ljubljana, Slovenia.
Iva
I
Hafner-Bratkovič
Department for the Production of Diagnostic Reagents and Research & R&D Service, Blood Transfusion Centre of Slovenia, Šlajmerjeva 6, SI-1000, Ljubljana, Slovenia. Electronic address: vladka.curin@ztm.si.
Vladka
V
Čurin Šerbec
D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure*; D001665:Binding Sites; D006863:Hydrogen-Ion Concentration; D000072002:Prion Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D013329:Structure-Activity Relationship
D000682:Amyloid; D000072002:Prion Proteins
Amyloid; Anchorless; Prion protein; Stop mutation; Truncation