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Pré-Publication, Document De Travail Année : 2023

The smallest infectious substructure encoding the prion strain structural determinant revealed by spontaneous dissociation of misfolded prion protein assemblies

Résumé

Abstract It is commonly accepted that the prion replicative propensity and strain structural determinant (SSD) are encoded in the fold of PrP Sc amyloid fibril assemblies. By exploring the quaternary structure dynamicity of several prion strains, we revealed that all mammalian prion assemblies exhibit the generic property of spontaneously generating two sets of discreet infectious tetrameric and dimeric species differing significantly by their specific infectivity. By using perturbation approaches such as dilution and ionic strength variation, we demonstrated that these two oligomeric species were highly dynamic and evolved differently in the presence of chaotropic agents. In general, our observations of seven different prion strains from three distinct species highlight the high dynamicity of PrP Sc assemblies as a common and intrinsic property of mammalian prions. The existence of such small infectious PrP Sc species harboring the SSD indicates that the prion infectivity and the SSD are not restricted only to the amyloid fold but can also be encoded in other alternative quaternary structures. Such diversity in the quaternary structure of prion assemblies tends to indicate that the structure of PrP Sc can be divided into two independent folding domains: a domain encoding the strain structural determinant and a second domain whose fold determines the type of quaternary structure that could adopt PrP Sc assemblies. Highlights Mammalian prion assemblies are highly dynamic Prion assemblies spontaneously disassemble into two infectious oligomers Prion infectivity is not exclusively encoded in the amyloid fibrils’ structure Two independent folding domains could structure Prion assemblies
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hal-04524637 , version 1 (28-03-2024)

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Jan Bohl, Mohammed Moudjou, Laetitia Herzog, Fabienne Reine, Fiona Sailler, et al.. The smallest infectious substructure encoding the prion strain structural determinant revealed by spontaneous dissociation of misfolded prion protein assemblies. 2024. ⟨hal-04524637⟩
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