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Mechanistic insights into cellular alteration of prion by poly-D-lysine: the role of H2H3 domain.

TitleMechanistic insights into cellular alteration of prion by poly-D-lysine: the role of H2H3 domain.
Publication TypeJournal Article
Year of Publication2011
AuthorsXu, Z, Adrover, M, Pastore, A, Prigent, S, Mouthon, F, Comoy, E, Rezaei, H, Deslys, J-P
JournalFASEB J
Date Published2011 Oct
KeywordsAnimals, Cell Line, Tumor, Mice, Models, Molecular, Polylysine, Protein Binding, Protein Folding, Protein Structure, Tertiary, PrPSc Proteins

Misfolding of the prion protein (PrP) is the central feature of prion diseases. The conversion of the normal α-helical PrP(C) into a pathological β-enriched PrP(Sc) constitutes an early event in the infectious process. Several hypotheses, involving different regions of the protein, endeavor to delineate the structural mechanism underlying this change of conformation. All current working hypotheses, however, are based on biophysical and modeling studies, the biological relevance of which still needs to be assessed. We have studied the effect of positively charged polymers on the conversion, using polylysine as a model system, and have investigated a possible mechanism of structural stabilization. We have shown that poly-D-lysine removes proteinase K-resistant PrP from prion-infected SN56 neuroblastoma cells without affecting PrP(C). The effect is enantiospecific since the levorotary isomer, poly-L-lysine, has a markedly weaker effect, likely because of its higher susceptibility to degradation. In vitro cross-linking and NMR studies confirm a direct interaction between polylysine and PrP, which mainly maps to the PrP region containing helices 2 and 3 (H2H3). Interaction prevents conformational conversion and protein aggregation. Our results establish a central role of H2H3 in PrP(Sc) amyloidogenesis and replication and provide biological relevance for the pathological misfolding of this domain.

Alternate JournalFASEB J.
PubMed ID21697549
Grant ListMC_U117533887 / / Medical Research Council / United Kingdom
MC_U117584256 / / Medical Research Council / United Kingdom

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