Quaternary Structure of Pathological Prion Protein as a Determining Factor of Strain-Specific Prion Replication Dynamics
PLoS Pathog. 2013-10-10; 9(10): e1003702
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1. PLoS Pathog. 2013;9(10):e1003702. doi: 10.1371/journal.ppat.1003702. Epub 2013
Quaternary structure of pathological prion protein as a determining factor of
strain-specific prion replication dynamics.
Laferrière F(1), Tixador P, Moudjou M, Chapuis J, Sibille P, Herzog L, Reine F,
Jaumain E, Laude H, Rezaei H, Béringue V.
(1)INRA (Institut National de la Recherche Agronomique), UR892, Virologie
Immunologie Moléculaires, Jouy-en-Josas, France.
Prions are proteinaceous infectious agents responsible for fatal
neurodegenerative diseases in animals and humans. They are essentially composed
of PrP(Sc), an aggregated, misfolded conformer of the ubiquitously expressed
host-encoded prion protein (PrP(C)). Stable variations in PrP(Sc) conformation
are assumed to encode the phenotypically tangible prion strains diversity.
However the direct contribution of PrP(Sc) quaternary structure to the strain
biological information remains mostly unknown. Applying a sedimentation velocity
fractionation technique to a panel of ovine prion strains, classified as fast and
slow according to their incubation time in ovine PrP transgenic mice, has
previously led to the observation that the relationship between prion infectivity
and PrP(Sc) quaternary structure was not univocal. For the fast strains
specifically, infectivity sedimented slowly and segregated from the bulk of
proteinase-K resistant PrP(Sc). To carefully separate the respective
contributions of size and density to this hydrodynamic behavior, we performed
sedimentation at the equilibrium and varied the solubilization conditions. The
density profile of prion infectivity and proteinase-K resistant PrP(Sc) tended to
overlap whatever the strain, fast or slow, leaving only size as the main
responsible factor for the specific velocity properties of the fast strain most
infectious component. We further show that this velocity-isolable population of
discrete assemblies perfectly resists limited proteolysis and that its templating
activity, as assessed by protein misfolding cyclic amplification outcompetes by
several orders of magnitude that of the bulk of larger size PrP(Sc) aggregates.
Together, the tight correlation between small size, conversion efficiency and
duration of disease establishes PrP(Sc) quaternary structure as a determining
factor of prion replication dynamics. For certain strains, a subset of PrP
assemblies appears to be the best template for prion replication. This has
important implications for fundamental studies on prions.
PMID: 24130496 [Indexed for MEDLINE]