Simulations of membrane‐bound diglycosylated human prion protein reveal potential protective mechanisms against misfolding

Abstract

Prion diseases are associated with the misfolding of the prion protein (PrP) from its normal cellular form (PrPC) to its infectious scrapie form (PrPSc). Posttranslational modifications of PrP in vivo can play an important role in modulating the process of misfolding. To gain more insight into the effects of posttranslational modifications on PrP structure and dynamics and to test the hypothesis that such modifications can interact with the protein, we have performed molecular dynamics simulations of diglycosylated human PrPC bound to a lipid bilayer via a glycophosphatidylinositol anchor. Multiple simulations were performed at three different pH ranges to explore pH effects on structure and dynamics. In contrast to simulations of protein-only PrPC, no large effects were observed upon lowering the pH of the system. The protein tilted toward the membrane surface in all of the simulations and the putative PrPSc oligomerization sites became inaccessible, thereby offering a possible protective mechanism against PrPSc-induced misfolding of PrPC.

Characterization of Lipid–Protein Interactions and Lipid-Mediated Modulation of Membrane Protein Function through Molecular Simulation

“…In contrast, when simulated at the surface of the membrane for ∼40−80 ns, PrPC remained stable because it tilted toward the membrane surface, rendering the putative sites for misfolding and oligomerization inaccessible. 598 Misfolding of Huntingtin protein is related to Huntington's disease through pathways that likely involve interactions with the membrane. The poly glutamine region of Huntingtin protein, with a variety of different flanking sequences, was found to induce a variety of membrane effects.…”

“…When simulated in solution, PrPC showed a tendency to misfold during AA simulations of 10–50 ns. In contrast, when simulated at the surface of the membrane for ∼40–80 ns, PrPC remained stable because it tilted toward the membrane surface, rendering the putative sites for misfolding and oligomerization inaccessible . Misfolding of Huntingtin protein is related to Huntington’s disease through pathways that likely involve interactions with the membrane.…”

Anchorless risk or released benefit? An updated view on the ADAM10-mediated shedding of the prion protein

“…Inlay shows a model of the conceivable Aβ (red) sequestrating and plaque-promoting action of sPrP (green). Respective non-coloured single channels are shown on the left (g′, g″, g‴) ◂ diglycosylated PrP was a rather poor substrate for the templated misfolding (Camacho et al 2019;Cheng et al 2017;DeMarco and Daggett 2009;Kang et al 2020;Priola and Lawson 2001;Xiao et al 2013). This may well translate into sPrP's blocking activity against the amplification of certain prion strains.…”

Atomic insights into the effects of pathological mutants through the disruption of hydrophobic core in the prion protein

“…In this study, we examined the first glycosylation motif, which determines the location of PrP in the cell. Many previous in-vitro and in-silico studies have shown the importance of PrP location in misfolding and aggregation 40,68,69 . The known mechanism for this is that the oligomerization sites are buried in the membrane surface, which prevents the oligomerization and propagation 69 of PrP SC .…”

“…Many previous in-vitro and in-silico studies have shown the importance of PrP location in misfolding and aggregation 40,68,69 . The known mechanism for this is that the oligomerization sites are buried in the membrane surface, which prevents the oligomerization and propagation 69 of PrP SC . The T183A mutant not only breaks the first glycosylation motif but also destabilizes the PrP T183A structure.…”