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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
1
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pubmed:dateCreated |
2009-3-18
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pubmed:abstractText |
The prion protein (PrP) is responsible for several fatal neurodegenerative diseases via conversion from its normal to disease-related isoform. The recombinant form of the protein is typically studied to investigate the conversion process. This constructs lacks the co- and post-translational modifications present in vivo, there the protein has two N-linked glycans and is bound to the outer leaflet of the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor. The inherent flexibility and heterogeneity of the glycans, the plasticity of the GPI anchor, and the localization of the protein in a membrane make experimental structural characterization of biological constructs of cellular prion protein (PrP(C)) challenging. Yet this characterization is central in determining not only the suitability of recombinant (rec)-PrP(C) as a model for biological forms of the protein but also the potential role of co- and post-translational modifications on the disease process. Here, we present molecular dynamics simulations of three human prion protein constructs: (i) a protein-only construct modeling the recombinant form, (ii) a diglycosylated and soluble construct, and (iii) a diglycosylated and GPI-anchored construct bound to a lipid bilayer. We found that glycosylation and membrane anchoring do not significantly alter the structure or dynamics of PrP(C), but they do appreciably modify the accessibility of the polypeptide surface PrP(C). In addition, the simulations of membrane-bound PrP(C) revealed likely recognition domains for the disease-initiating PrP(C):PrP(Sc) (infectious and/or misfolded form of the prion protein) binding event and a potential mechanism for the observed inefficiency of conversion associated with differentially glycosylated PrP species.
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pubmed:grant |
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pubmed:commentsCorrections |
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http://linkedlifedata.com/resource/pubmed/commentcorrection/19226372-9721914
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
1471-4159
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
109
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
60-73
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pubmed:dateRevised |
2011-9-26
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pubmed:meshHeading |
pubmed-meshheading:19226372-Animals,
pubmed-meshheading:19226372-Cell Membrane,
pubmed-meshheading:19226372-Computer Simulation,
pubmed-meshheading:19226372-Glycosylation,
pubmed-meshheading:19226372-Humans,
pubmed-meshheading:19226372-Membrane Proteins,
pubmed-meshheading:19226372-Mice,
pubmed-meshheading:19226372-Models, Molecular,
pubmed-meshheading:19226372-Prions,
pubmed-meshheading:19226372-Protein Binding,
pubmed-meshheading:19226372-Protein Biosynthesis,
pubmed-meshheading:19226372-Protein Folding,
pubmed-meshheading:19226372-Rats,
pubmed-meshheading:19226372-Recombinant Proteins
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pubmed:year |
2009
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pubmed:articleTitle |
Characterization of cell-surface prion protein relative to its recombinant analogue: insights from molecular dynamics simulations of diglycosylated, membrane-bound human prion protein.
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pubmed:affiliation |
Biomolecular Structure and Design Program, University of Washington, Seattle, Washington, USA.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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