Binding of disease-associated prion protein to plasminogen

Transmissible spongiform encephalopathies are associated with accumulation of PrPSc, a conformer of a cellular protein called PrPC. PrPSc is thought t o replicate by imparting its conformation onto PrPC (ref. 1), yet conformat ional discrimination between PrPC and PrPSc has remained elusive. Because d eposition of PrPSc alone is not enough to cause neuropathology(2), PrPSc pr obably damages the brain by interacting with other cellular constituents. H ere we rnd activities in human and mouse blood which bind PrPSc and prion i nfectivity, but not PrPC. We identify plasminogen, a pro-protease implicate d in neuronal excitotoxicity(3,4), as a PrPSc-binding protein. Binding is a bolished if the conformation of PrPSc is disrupted by 6M urea or guanidine. The isolated lysine binding site 1 of plasminogen (kringles I-III) retains this binding activity, and binding can be competed for with lysine. Theref ore, plasminogen represents the first endogenous factor discriminating betw een normal and pathological prion protein. This unexpected property may be exploited for diagnostic purposes.