NR ATIQ
AU Epple,G.; Schwiem,U.; Kettelgerdes,G.; Köttgen,E.; Geßner,R.; Praus,M.
TI Interaction of the cellular prion protein with the fibrinolytic system
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Cell Biology of PrPc and PrPsc CELL-48
PT Konferenz-Poster
AB
The pathological conformer of the human prion protein binds tightly to human plasminogen (1). The binding is, however, not specific for the pathological conformer (2,3). Plasmin is able to cleave recombinant PrPc at lysine residue 110 (2,3). The generated NH2-terminal truncated molecule has been described to be a product of normal PrPc metabolism (4). The NH2-terminal part of PrPc (PrP23-110) stimulates t-PA mediated plasminogen activation in vitro (5,6). PrPc binds to plasminogen activators that carry kringle domains i.e. t-PA, u-PA and DSPA. However, binding is not sufficient to stimulate plasmin generation since only t-PA, that carries a lysine-binding site in kringle 2 is stimulated by PrP (3).
Here we show, that site-directed mutagenesis altering the plasmin cleavage site reduce plasminogen activation and cleavage by plasmin. The banding patterns on SDS-PAGE implicate an additional cleavage site in PrPc located in the conserved helix 1-region. This region is structurally conserved between birds, reptiles, amphibians and mammals. As the helix 1 has no apparent role in stabilization of the protein fold, this motive might be conserved for reasons of protein function (7). In conclusion our data support our hypothesis, that PrPc plays a role in the regulation of cellular proteolysis in the CNS
1. Fischer, M. B., et al. (2000) Nature 408, 479-483.
2. Kornblatt, J. A., et al. (2003) Biochem Biophys Res Commun 305, 518-522.
3. Epple, G., et al. (2004) J Thromb Haemost 2, 962-968
4. Chen, S. G., et al. (1995) J. Biol. Chem. 270, 19173-19180
5. Praus, M., et al. (2003) Thromb Haemost 89, 812-819.
6. Epple, G., et al. (2004) Thromb Haemost 91, 465-472
7. Calzolai, L., et al. (2005) PNAS 102, 651-655
AD G.Epple, U.Schwiem, G.Kettelgerdes, E.Köttgen, R.Geßner, M.Praus, Institute of Laboratory Medicine, Charité Medical School Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
SP englisch
PO Deutschland