title: Binding of disease-associated prion protein to plasminogen.
abstract: Transmissible spongiform encephalopathies are associated with accumulation of PrP(Sc), a conformer of a cellular protein called PrP(C). PrP(Sc) is thought to replicate by imparting its conformation onto PrP(C) (ref. 1), yet conformational discrimination between PrP(C) and PrP(Sc) has remained elusive. Because deposition of PrP(Sc) alone is not enough to cause neuropathology, PrP(Sc) probably damages the brain by interacting with other cellular constituents. Here we find activities in human and mouse blood which bind PrP(Sc) and prion infectivity, but not PrP(C). We identify plasminogen, a pro-protease implicated in neuronal excitotoxicity, as a PrP(Sc)-binding protein. Binding is abolished if the conformation of PrP(Sc) 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.
authors: Institute for Neuropatholgy, University Hospital of Zurich, Switzerland.
authors: M B
authors: MB
authors: Fischer
authors: C
authors: C
authors: Roeckl
authors: P
authors: P
authors: Parizek
authors: H P
authors: HP
authors: Schwarz
authors: A
authors: A
authors: Aguzzi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019791:Guanidine; D006801:Humans; D008280:Magnetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010958:Plasminogen / Q000378:metabolism*; D018622:PrP 27-30 Protein / Q000378:metabolism; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014508:Urea
chemical_list: D018620:PrPSc Proteins; D018622:PrP 27-30 Protein; D014508:Urea; D010958:Plasminogen; D019791:Guanidine