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Biophys J. 2015 Nov 17;109(10):2090-100. doi: 10.1016/j.bpj.2015.10.009.

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

Author information

1
Department of Molecular Biosciences and Center for Bioinformatics, The University of Kansas, Lawrence, Kansas.
2
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland; Department of Chemistry, Indian Institute of Technology Gandhinagar, Chandkheda, Ahmedabad, Gujarat, India.
3
Department of Chemistry, Indian Institute of Technology Gandhinagar, Chandkheda, Ahmedabad, Gujarat, India.
4
Department of Chemical and Biomolecular Engineering and the Biophysics Program, The University of Maryland, College Park, Maryland.
5
Department of Molecular Biosciences and Center for Bioinformatics, The University of Kansas, Lawrence, Kansas. Electronic address: wonpil@ku.edu.

Abstract

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.

PMID:
26588568
PMCID:
PMC4656879
DOI:
10.1016/j.bpj.2015.10.009
[Indexed for MEDLINE]
Free PMC Article

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