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

Abstract

AbstractIt is commonly accepted that the prion replicative propensity and strain structural determinant (SSD) are encoded in the fold of PrPScamyloid 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 PrPScassemblies as a common and intrinsic property of mammalian prions. The existence of such small infectious PrPScspecies 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 PrPSccan 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 PrPScassemblies.HighlightsMammalian prion assemblies are highly dynamicPrion assemblies spontaneously disassemble into two infectious oligomersPrion infectivity is not exclusively encoded in the amyloid fibrils’ structureTwo independent folding domains could structure Prion assemblies