Abstract
BackgroundAn increasing number of proteins are being shown to assemble into amyloid structures that lead to pathological states. Among them, mammalian prions outstand due to their ability to transmit the pathogenic conformation, becoming thus infectious. The structural conversion of the cellular prion protein (PrPC), into its misfolded pathogenic form (PrPSc) is the central event of prion-driven pathologies. The study of the structural properties of intracellular amyloid aggregates in general and of prion-like ones in particular is a challenging task. In this context, the evidence that the inclusion bodies formed by amyloid proteins in bacteria display amyloid-like structural and functional properties make them a privileged system to model intracellular amyloid aggregation.ResultsHere we provide the first demonstration that recombinant murine PrP and its C-terminal domain (90–231) attain amyloid conformations inside bacteria. Moreover, the inclusions formed by these two PrP proteins display conformational diversity, since they differ in fibril morphology, binding affinity to amyloid dyes, stability, resistance to proteinase K digestion and neurotoxicity.ConclusionsOverall, our results suggest that modelling PrP amyloid formation in microbial cell factories might open an avenue for a better understanding of the structural features modulating the pathogenic impact of this intriguing protein.Electronic supplementary materialThe online version of this article (doi:10.1186/s12934-015-0361-y) contains supplementary material, which is available to authorized users.
Highlights
An increasing number of proteins are being shown to assemble into amyloid structures that lead to pathological states
To verify if this is the case for mammalian prion proteins, we expressed the murine wild-type prion protein (PrPWT) encompassing residues 23-231 (PrPWT) and the C-terminal domain of murine PrP (PrP90–231) in bacteria and purified the resulting Inclusion bodies (IBs)
The N-terminal unstructured domain is proposed to participate in PrP physiological function because of its ability to bind to different classes of partners, including copper ions (Cu2+), glycosaminoglycans (GAGs), nucleic acids (NAs) and lipids [33,34,35,36,37,38]
Summary
An increasing number of proteins are being shown to assemble into amyloid structures that lead to pathological states. The structural conversion of the cellular prion protein (PrPC), into its misfolded pathogenic form (PrPSc) is the central event of prion-driven pathologies. The study of the structural properties of intracellular amyloid aggregates in general and of prion-like ones in particular is a challenging task. TSEs form a group of lethal neurodegenerative disorders, which affect both humans and other mammals [3]. They may manifest as infectious, genetic or sporadic diseases. The structural conversion of the cellular prion protein (PrPC), into its misfolded pathogenic form (PrPSc) is the central event of these pathologies. Unlike PrPC, PrPSc is an insoluble protein, mainly composed by β-sheet structures, partially resistant to proteolysis, with a high propensity to Macedo et al Microb Cell Fact (2015) 14:174
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