Binding of disease-associated prion protein to plasminogen

• Published in: Nature (London) Vol. 408; no. 6811; pp. 479 - 483
• Main Authors: Aguzzi, Adriano, Fischer, Michael B, Roeckl, Christiane, Parizek, Petra, Schwarz, Hans Peter
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 23.11.2000; Nature Publishing Group
• Subjects: Animals; Biological and medical sciences; Blotting, Western; Brain; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease; Guanidine; Humans; Magnetics; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurology; plasminogen; Plasminogen - metabolism; Prion Diseases - metabolism; Protein Binding; Protein Conformation; Proteins; PrP 27-30 Protein - metabolism; PrPSc Proteins - chemistry; PrPSc Proteins - metabolism; Structure-Activity Relationship; Urea; Human; Ligand binding; Nervous system diseases; Pathogenesis; Rodentia; Cerebral disorder; Infection; Protein PrP; Vertebrata; Mammalia; Mouse; Animal; Central nervous system disease; Degenerative disease; Prion; Plasminogen; Creutzfeldt Jakob disease
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/35044100

Transmissible spongiform encephalopathies are associated with accumulation of PrPSc, a conformer of a cellular protein called PrP C. PrPSc is thought to replicate by imparting its conformation onto PrPC (ref. 1), yet conformational discrimination between PrPC and PrPSc has remained elusive. Because deposition of PrPSc alone is not enough to cause neuropathology, PrPSc probably damages the brain by interacting with other cellular constituents. Here we find activities in human and mouse blood which bind PrPSc and prion infectivity, but not PrPC. We identify plasminogen, a pro-protease implicated in neuronal excitotoxicity, as a PrPSc-binding protein. Binding is abolished 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. Therefore, plasminogen represents the first endogenous factor discriminating between normal and pathological prion protein. This unexpected property may be exploited for diagnostic purposes.