Insight into Early-Stage Unfolding of GPI-Anchored Human Prion Protein.

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TitleInsight into Early-Stage Unfolding of GPI-Anchored Human Prion Protein.
Publication TypeJournal Article
Year of Publication2015
AuthorsWu, EL, Qi, Y, Park, S, Mallajosyula, SS, Mackerell, AD, Klauda, JB, Im, W
JournalBiophys J
Date Published2015 Nov 17
KeywordsAmino Acid Sequence, Glycosylphosphatidylinositols, Humans, Molecular Dynamics Simulation, Molecular Sequence Data, Protein Binding, Protein Structure, Tertiary, Protein Unfolding, PrPSc Proteins

Prion diseases are fatal neurodegenerative disorders, which are characterized by the accumulation of misfolded prion protein (PrPSc) converted from a normal host cellular prion protein (PrPC). Experimental studies suggest that PrPC is enriched with α-helical structure, whereas PrPSc contains a high proportion of β-sheet. In this study, we report the impact of N-glycosylation and the membrane on the secondary structure stability utilizing extensive microsecond molecular dynamics simulations. Our results reveal that the HB (residues 173 to 194) C-terminal fragment undergoes conformational changes and helix unfolding in the absence of membrane environments because of the competition between protein backbone intramolecular and protein-water intermolecular hydrogen bonds as well as its intrinsic instability originated from the amino acid sequence. This initiation of the unfolding process of PrPC leads to a subsequent increase in the length of the HB-HC loop (residues 195 to 199) that may trigger larger rigid body motions or further unfolding around this region. Continuous interactions between prion protein and the membrane not only constrain the protein conformation but also decrease the solvent accessibility of the backbone atoms, thereby stabilizing the secondary structure, which is enhanced by N-glycosylation via additional interactions between the N-glycans and the membrane surface.

Alternate JournalBiophys. J.
PubMed ID26588568
PubMed Central IDPMC4656879
Grant ListR01 GM070855 / GM / NIGMS NIH HHS / United States
U54 GM087519 / GM / NIGMS NIH HHS / United States
GM070855 / GM / NIGMS NIH HHS / United States
P41 GM103712 / GM / NIGMS NIH HHS / United States
P41GM103712-S1 / GM / NIGMS NIH HHS / United States