Binding of disease-associated prion protein to plasminogen

Article metrics

Abstract

Transmissible spongiform encephalopathies are associated with accumulation of PrPSc, a conformer of a cellular protein called PrPC. 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 neuropathology2, 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 excitotoxicity3,4, 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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Western blot analysis of serum factors that interact with disease-associated prion protein.
Figure 2: Partial purification of PrPB.
Figure 3: Characterization of the PrPSc binding activity of plasminogen.
Figure 4: The mechanism by which plasminogen binds PrPSc and prion infectivity.

References

  1. 1

    Prusiner, S. B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 ( 1982).

  2. 2

    Brandner, S. et al. Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature 379, 339–343 (1996).

  3. 3

    Chen, Z. L. & Strickland, S. Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 91, 917–925 (1997).

  4. 4

    Tsirka, S. E., Rogove, A. D. & Strickland, S. Neuronal cell death and tPA. Nature 384, 123–124 (1996).

  5. 5

    Büeler, H. R. et al. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356, 577 –582 (1992).

  6. 6

    Korth, C. et al. Prion (PrPSc)-specific epitope defined by a monoclonal antibody. Nature 390, 74– 77 (1997).

  7. 7

    Prusiner, S. B. & Scott, M. R. Genetics of prions. Annu. Rev. Genet. 31, 139– 175 (1997).

  8. 8

    Fischer, M. et al. Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie. EMBO J. 15, 1255–1264 (1996).

  9. 9

    Riek, R. et al. NMR structure of the mouse prion protein domain Prp(121–231). Nature 382, 180–182 (1996).

  10. 10

    Riek, R., Hornemann, S., Wider, G., Glockshuber, R. & Wüthrich, K. NMR characterization of the full-length recombinant murine prion protein, mPrP(23–231). FEBS Lett. 413, 282–288 (1997).

  11. 11

    Shibuya, S., Higuchi, J., Shin, R. W., Tateishi, J. & Kitamoto, T. Protective prion protein polymorphisms against sporadic Creutzfeldt- Jakob disease. Lancet 351, 419 (1998).

  12. 12

    Zulianello, L. et al. Dominant-negative inhibition of prion formation diminished by deletion mutagenesis of the prion protein. J. Virol. 74, 4351–4360 (2000).

  13. 13

    Telling, G. C. et al. Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 83, 79–90 (1995).

  14. 14

    Kaneko, K. et al. Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation. Proc. Natl Acad. Sci. USA 94, 10069– 10074 (1997).

  15. 15

    Madani, R. et al. Enhanced hippocampal long-term potentiation and learning by increased neuronal expression of tissue-type plasminogen activator in transgenic mice. EMBO J. 18, 3007– 3012 (1999).

  16. 16

    Baranes, D. et al. Tissue plasminogen activator contributes to the late phase of LTP and to synaptic growth in the hippocampal mossy fiber pathway. Neuron 21, 813–825 ( 1998).

  17. 17

    Ledesma, M. D. et al. Brain plasmin influences APP alpha-cleavage and Aβ degradation and is reduced in Alzheimer's disease brains. EMBO Rep. (in the press).

  18. 18

    Naslavsky, N., Stein, R., Yanai, A., Friedlander, G. & Taraboulos, A. Characterization of detergent-insoluble complexes containing the cellular prion protein and its scrapie isoform. J. Biol. Chem. 272, 6324–6331 ( 1997).

  19. 19

    Houston, F., Foster, J. D., Chong, A., Hunter, N. & Bostock, C. J. Transmission of BSE by blood transfusion in sheep. Lancet 356, 999–1000 (2000).

  20. 20

    Prusiner, S. B. et al. Measurement of the scrapie agent using an incubation time interval assay. Ann. Neurol. 11, 353– 358 (1982).

Download references

Acknowledgements

We are grateful to D. Voelkel for providing fractionated human plasma, to P. Sonderegger, C. Weissmann, T. Lührs, and W. Schaffner for critical advice, and to M. Maissen and R. Hardegger for experimental help. This study was supported by grants from the European Union (Bundesamt für Bildung und Wissenschaft), the Swiss National Research Programs to A.A. and by a grant-in-aid of the SigmaXi foundation to M.B.F.

Author information

Correspondence to Adriano Aguzzi.

Rights and permissions

Reprints and Permissions

About this article

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.