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

Nature Structural Biology volume 8, pages 770–774 (2001)Cite this article

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.

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Figure 1: The human prion protein dimer.
Figure 2: Comparison of the human prion protein dimer (crystal structure) and monomer (NMR structure).
Figure 3: Stereo view of 29.0–2.0 Å resolution omit |Fo| − |Fc| electron density contoured at 2 σ for the two antiparallel β-strands containing residues Thr 188–Gly195 in the switch region at the prion protein dimer interface.
Figure 4: Mapping of residues relevant to disease transmission to the prion dimer structure, shown as a stereo Cα trace.

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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.

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Authors and Affiliations

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

    Karen J. Knaus & Vivien C. Yee

  2. Department of Chemistry, Cleveland State University, Cleveland, 44115, Ohio, USA

    Karen J. Knaus & Vivien C. Yee

  3. Department of Pathology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, 44106, Ohio, USA

    Manuel Morillas, Wieslaw Swietnicki & Witold K. Surewicz

  4. Department of Pharmacology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, 44106, Ohio, USA

    Michael Malone & Vivien C. Yee

  5. Department of Chemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, 44106, Ohio, USA

    Witold K. Surewicz

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

    Witold K. Surewicz

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  1. Karen J. Knaus
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Correspondence to Vivien C. Yee.

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Knaus, K., Morillas, M., Swietnicki, W. et al. Crystal structure of the human prion protein reveals a mechanism for oligomerization. Nat Struct Mol Biol 8, 770–774 (2001). https://doi.org/10.1038/nsb0901-770

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