Insight into early-stage unfolding of GPI-anchored human prion protein

Show simple item record Wu, Emilia L. Qi, Yifei Park, Soohyung Mallajosyula, Sairam Swaroop MacKerell, Alexander D. Klauda, Jeffery B. Im, Wonpil 2015-11-29T11:34:28Z 2015-11-29T11:34:28Z 2015-11
dc.identifier.citation Wu, Emilia L.; Qi, Yifei; Park, Soohyung; Mallajosyula, Sairam S.; MacKerell Jr., Alexander D.; Klauda, Jeffery B. and Im, Wonpil, “Insight into early-stage unfolding of GPI-anchored human prion protein”, Biophysical Journal, DOI: 10.1016/j.bpj.2015.10.009, vol. 109, no. 10, pp. 2090-2100, Nov. 2015. en_US
dc.description.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. en_US
dc.description.statementofresponsibility by Sairam S Mallajosyula et. al.
dc.format.extent Vol. 109, No. 10, pp. 2090-2100
dc.language.iso en_US en_US
dc.publisher Elsevier en_US
dc.subject Early-Stage Unfolding en_US
dc.subject Human Prion Protein en_US
dc.subject GPI-Anchored
dc.title Insight into early-stage unfolding of GPI-anchored human prion protein en_US
dc.type Article en_US
dc.relation.journal Biophysical Journal

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