Plasminogen: A cellular protein cofactor for PrPSc propagation


The biochemical essence of prion replication is the molecular multiplication of the disease-associated misfolded isoform of prion protein (PrP), termed PrPSc, in a nucleic acid-free manner. PrPSc is generated by the protein misfolding process facilitated by conformational conversion of the host-encoded cellular PrP to PrPSc. Evidence suggests that an auxiliary factor may play a role in PrPSc propagation. We and others previously discovered that plasminogen interacts with PrP, while its functional role for PrPSc propagation remained undetermined. In our recent in vitro PrP conversion study, we showed that plasminogen substantially stimulates PrPSc propagation in a concentration-dependent manner by accelerating the rate of PrPSc generation, while depletion of plasminogen, destabilization of its structure, and interference with the PrP-plasminogen interaction hinder PrPSc propagation. Further investigation in cell culture models confirmed an increase of PrPSc formation by plasminogen. Although molecular basis of the observed activity for plasminogen remain to be addressed, our results demonstrate that plasminogen is the first cellular protein auxiliary factor proven to stimulate PrPSc propagation.

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Plasminogen: A cellular protein cofactor for PrPSc propagation