Originally Posted on Scientific Reports | 31 March 2017
Microcin E492 (Mcc) is a pore-forming bacteriotoxin. Mcc activity is inhibited at the stationary phase by formation of amyloid-like aggregates in the culture. Here we report that, in a similar manner as prions, Mcc naturally exists as two conformers: a β-sheet-rich, protease-resistant, aggregated, inactive form (Mccia), and a soluble, protease-sensitive, active form (Mcca).
The exogenous addition of culture medium containing Mccia or purified in vitro-generated Mccia into the culture induces the rapid and efficient conversion of Mcca into Mccia, which is maintained indefinitely after passaging, changing the bacterial phenotype. Mccia prion-like activity is conformation-dependent and could be reduced by immunodepleting Mccia. Interestingly, an internal region of Mcc shares sequence similarity with the central domain of the prion protein, which is key to the formation of mammalian prions. A synthetic peptide spanning this sequence forms amyloid-like fibrils in vitro and is capable of inducing the conversion of Mcca into Mccia in vivo, suggesting that this region corresponds to the prion domain of Mcc.
Our findings suggest that Mcc is the first prokaryotic protein with prion properties which harnesses prion-like transmission to regulate protein function, suggesting that propagation of biological information using a prion-based conformational switch is an evolutionary conserved mechanism.
Prions are the infectious agents responsible for a group of neurodegenerative diseases, termed prion diseases or transmissible spongiform encephalopathies (TSEs), including scrapie, chronic wasting disease, bovine spongi-form encephalopathy, and Creutzfeldt-Jakob disease. The main component of a prion is a misfolded form of the normal host-encoded prion protein (PrPC) capable of self-perpetuating by converting PrPC into the pathological, infectious form (PrPSc). Although the molecular mechanism through which conversion of PrPC to PrPSc occurs is poorly understood, the experimental evidence suggests a direct interaction of PrPC with pre-existing oligomeric PrPSc, which acts as a seed to induce the recruitment of the normal protein into the aggregate, templating the conformational conversion of PrPC into PrPSc. The conversion is associated with an increase in β -sheet structure, insolubility in ionic detergents, resistance to proteolytic degradation, and the formation of amyloid-like aggregates.
In vitro, prion protein polymerizes through a nucleation-dependent process, which is composed of a lag phase followed by an extension phase. The lag phase can be reduced or removed either by increasing protein concentration or by the addition of preformed aggregates. In vivo, injection or ingestion of purified PrPSc or tissue extracts containing PrPSc from infected animals leads to the pathological conversion of host PrPC into PrPSc and the development of prion disease. Thus, the seeding/nucleation mechanism offers a plausible model for the infectious nature of prions.
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