Letter | Published:

Crystal structure of the human prion protein reveals a mechanism for oligomerization

Nature Structural Biology volume 8, pages 770774 (2001) | Download Citation

Subjects

Abstract

The pathogenesis of transmissible encephalopathies is associated with the conversion of the cellular prion protein, PrPC, into a conformationally altered oligomeric form, PrPSc. Here we report the crystal structure of the human prion protein in dimer form at 2 Å resolution. The dimer results from the three-dimensional swapping of the C-terminal helix 3 and rearrangement of the disulfide bond. An interchain two-stranded antiparallel β-sheet is formed at the dimer interface by residues that are located in helix 2 in the monomeric NMR structures. Familial prion disease mutations map to the regions directly involved in helix swapping. This crystal structure suggests that oligomerization through 3D domain-swapping may constitute an important step on the pathway of the PrPC → PrPSc conversion.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Protein Data Bank

References

  1. 1.

    Proc. Natl. Acad. Sci. USA 95, 13363–13383 (1998).

  2. 2.

    & Cell 89, 499–510 (1997).

  3. 3.

    et al. Nature 389, 498–501 (1997).

  4. 4.

    et al. Biochemistry 30, 7672–7680 (1991).

  5. 5.

    et al. Nature 382, 180–182 (1996).

  6. 6.

    et al. Proc. Natl. Acad. Sci. USA 94, 13452–13457 (1997).

  7. 7.

    et al. Proc. Natl. Acad. Sci. USA 97, 145–150 (2000).

  8. 8.

    , , & Proc. Natl. Acad. Sci. USA 97, 8334–8339 (2000).

  9. 9.

    , , & J. Biol. Chem. 274, 36859–36865 (1999).

  10. 10.

    , & FEBS Lett. 417, 400–404 (1997).

  11. 11.

    , , , & Biochemistry 39, 424–431 (2000).

  12. 12.

    & J. Biol. Chem. 176, 2427–2431 (2001).

  13. 13.

    , , , & J. Biol. Chem. 275, 33650–33654 (2000).

  14. 14.

    , & Proc. Natl. Acad. Sci. USA 91, 3127–3131 (1994).

  15. 15.

    et al. Nature Struct. Biology 8, 316–320 (2001).

  16. 16.

    et al. Proc. Natl. Acad. Sci. USA 89, 1870–1874 (1992).

  17. 17.

    & J. Mol. Biol. 234, 946–950 (1993).

  18. 18.

    , & J. Mol. Biol. 285, 2177–2198 (1999).

  19. 19.

    et al. In Prion biology and diseases (ed. Prusiner, S.B.) 509–583 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; 1999).

  20. 20.

    et al. Proc. Natl. Acad. Sci. USA 94, 10069–10074 (1997).

  21. 21.

    , , Cell 73, 1055–1058 (1993).

  22. 22.

    , , & J. Biol. Chem. 270, 3299–3305 (1995).

  23. 23.

    & Methods Enzymol. 276, 307–326 (1997).

  24. 24.

    & Acta Crystallogr. D 55, 849–861 (1999).

  25. 25.

    & Methods Enzymol. 276, 472–494 (1997).

  26. 26.

    Collaborative Computational Project, Number 4. Acta Crystallogr. D 50, 760–763 (1994).

  27. 27.

    , , & Acta Crystallogr.A 47, 110–119 (1991).

  28. 28.

    et al. Acta Crystallogr. D 54, 905–921 (1998).

  29. 29.

    J. Appl. Crystallogr.. 24, 946–950 (1991).

  30. 30.

    Acta Crystallogr. D 55, 938–940 (1999).

  31. 31.

    & Methods Enzymol. 277, 505–524 (1997).

  32. 32.

    , & Proteins 11, 281–296 (1991).

Download references

Acknowledgements

Diffraction data were measured at APS beamline 19-ID and at ALS beamline 5.0.2., both supported by the US DOE, and at BNL NSLS beamline X25, supported by the U.S. DOE and the NIH. We are grateful to the CCF/LRI Computer Core for facilities support, to S. Ginell and T. Earnest for beamline support and especially to F. van den Akker for many helpful discussions. This work was supported by grants from the NSF and AHA to V.C.Y. and from the NIH to W.K.S.

Author information

Affiliations

  1. Department of Molecular Cardiology and Center for Structural Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue NB20, Cleveland, Ohio 44195, USA.

    • Karen J. Knaus
    •  & Vivien C. Yee
  2. Department of Chemistry, Cleveland State University, Cleveland, Ohio 44115, USA.

    • Karen J. Knaus
    •  & Vivien C. Yee
  3. Department of Pathology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.

    • Manuel Morillas
    • , Wieslaw Swietnicki
    •  & Witold K. Surewicz
  4. Department of Pharmacology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.

    • Michael Malone
    •  & Vivien C. Yee
  5. Department of Chemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.

    • Witold K. Surewicz
  6. Department of Physiology and Biophysics, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.

    • Witold K. Surewicz

Authors

  1. Search for Karen J. Knaus in:

  2. Search for Manuel Morillas in:

  3. Search for Wieslaw Swietnicki in:

  4. Search for Michael Malone in:

  5. Search for Witold K. Surewicz in:

  6. Search for Vivien C. Yee in:

Corresponding author

Correspondence to Vivien C. Yee.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nsb0901-770

Further reading