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Atomic structures of amyloid cross-β spines reveal varied steric zippers

Nature volume 447, pages 453–457 (2007)Cite this article

Abstract

Amyloid fibrils formed from different proteins, each associated with a particular disease, contain a common cross-β spine. The atomic architecture of a spine, from the fibril-forming segment GNNQQNY of the yeast prion protein Sup35, was recently revealed by X-ray microcrystallography. It is a pair of β-sheets, with the facing side chains of the two sheets interdigitated in a dry ‘steric zipper’. Here we report some 30 other segments from fibril-forming proteins that form amyloid-like fibrils, microcrystals, or usually both. These include segments from the Alzheimer’s amyloid-β and tau proteins, the PrP prion protein, insulin, islet amyloid polypeptide (IAPP), lysozyme, myoglobin, α-synuclein and β2-microglobulin, suggesting that common structural features are shared by amyloid diseases at the molecular level. Structures of 13 of these microcrystals all reveal steric zippers, but with variations that expand the range of atomic architectures for amyloid-like fibrils and offer an atomic-level hypothesis for the basis of prion strains.

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Figure 1: Amyloid fibrils and microcrystals.
Figure 2: Thirteen atomic-resolution structures for peptide segments of fibril-forming proteins.
Figure 3: 3D views of representative steric zipper structures of classes 1, 2, 4 and 7, showing the front sheet in silver and the rear sheet in purple.
Figure 4: The eight classes of steric zippers.

References

  1. Westermark, P. Aspects on human amyloid forms and their fibril polypeptides. FEBS J. 272, 5942–5949 (2005)

    Article  CAS  Google Scholar 

  2. Westermark, P. et al. Amyloid: toward terminology clarification. Report from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid 12, 1–4 (2005)

    Article  CAS  Google Scholar 

  3. Cohen, A. S. & Calkins, E. Electron microscopic observations on a fibrous component in amyloid of diverse origins. Nature 183, 1202–1203 (1959)

    Article  ADS  CAS  Google Scholar 

  4. Rochet, J. C. & Lansbury, P. T. Jr. Amyloid fibrillogenesis: themes and variations. Curr. Opin. Struct. Biol. 10, 60–68 (2000)

    Article  CAS  Google Scholar 

  5. Astbury, W. T., Dickinson, S. & Bailey, K. The X-ray interpretation of denaturation and the structure of the seed globulins. Biochem. J. 29, 2351–2360 (1935)

    Article  CAS  Google Scholar 

  6. Geddes, A. J., Parker, K. D., Atkins, E. D. & Beighton, E. “Cross-β” conformation in proteins. J. Mol. Biol. 32, 343–358 (1968)

    Article  CAS  Google Scholar 

  7. Sunde, M. & Blake, C. The structure of amyloid fibrils by electron microscopy and X-ray diffraction. Adv. Protein Chem. 50, 123–159 (1997)

    Article  CAS  Google Scholar 

  8. Eanes, E. D. & Glenner, G. G. X-ray diffraction studies on amyloid filaments. J. Histochem. Cytochem. 16, 673–677 (1968)

    Article  CAS  Google Scholar 

  9. Sunde, M. et al. Common core structure of amyloid fibrils by synchrotron X-ray diffraction. J. Mol. Biol. 273, 729–739 (1997)

    Article  CAS  Google Scholar 

  10. Ritter, C. et al. Correlation of structural elements and infectivity of the HET-s prion. Nature 435, 844–848 (2005)

    Article  ADS  CAS  Google Scholar 

  11. Sikorski, P. & Atkins, E. New model for crystalline polyglutamine assemblies and their connection with amyloid fibrils. Biomacromolecules 6, 425–432 (2005)

    Article  CAS  Google Scholar 

  12. Petkova, A. T. et al. A structural model for Alzheimer’s β-amyloid fibrils based on experimental constraints from solid state NMR. Proc. Natl Acad. Sci. USA 99, 16742–16747 (2002)

    Article  ADS  CAS  Google Scholar 

  13. Jaroniec, C. P. et al. High-resolution molecular structure of a peptide in an amyloid fibril determined by magic angle spinning NMR spectroscopy. Proc. Natl Acad. Sci. USA 101, 711–716 (2004)

    Article  ADS  CAS  Google Scholar 

  14. Krishnan, R. & Lindquist, S. L. Structural insights into a yeast prion illuminate nucleation and strain diversity. Nature 435, 765–772 (2005)

    Article  ADS  CAS  Google Scholar 

  15. Makin, O. S. & Serpell, L. C. Structures for amyloid fibrils. FEBS J. 272, 5950–5961 (2005)

    Article  CAS  Google Scholar 

  16. Lührs, T. et al. 3D structure of Alzheimer’s amyloid-β(1–42) fibrils. Proc. Natl Acad. Sci. USA 102, 17342–17347 (2005)

    Article  ADS  Google Scholar 

  17. Török, M. et al. Structural and dynamic features of Alzheimer’s Aβ peptide in amyloid fibrils studied by site-directed spin labeling. J. Biol. Chem. 277, 40810–40815 (2002)

    Article  Google Scholar 

  18. Paravastu, A. K., Petkova, A. T. & Tycko, R. Polymorphic fibril formation by residues 10–40 of the Alzheimer’s β-amyloid peptide. Biophys. J. 90, 4618–4629 (2006)

    Article  ADS  CAS  Google Scholar 

  19. Williams, A. D. et al. Mapping Aβ amyloid fibril secondary structure using scanning proline mutagenesis. J. Mol. Biol. 335, 833–842 (2004)

    Article  CAS  Google Scholar 

  20. Kheterpal, I., Zhou, S., Cook, K. D. & Wetzel, R. Aβ amyloid fibrils possess a core structure highly resistant to hydrogen exchange. Proc. Natl Acad. Sci. USA 97, 13597–13601 (2000)

    Article  ADS  CAS  Google Scholar 

  21. Ferguson, N. et al. General structural motifs of amyloid protofilaments. Proc. Natl Acad. Sci. USA 103, 16248–16253 (2006)

    Article  ADS  CAS  Google Scholar 

  22. Nelson, R. et al. Structure of the cross-β spine of amyloid-like fibrils. Nature 435, 773–778 (2005)

    Article  ADS  CAS  Google Scholar 

  23. Balbirnie, M., Grothe, R. & Eisenberg, D. S. An amyloid-forming peptide from the yeast prion Sup35 reveals a dehydrated β-sheet structure for amyloid. Proc. Natl Acad. Sci. USA 98, 2375–2380 (2001)

    Article  ADS  CAS  Google Scholar 

  24. Diaz-Avalos, R. et al. Cross-β order and diversity in nanocrystals of an amyloid-forming peptide. J. Mol. Biol. 330, 1165–1175 (2003)

    Article  CAS  Google Scholar 

  25. Baxa, U. et al. Architecture of Ure2p prion filaments: the N-terminal domains form a central core fiber. J. Biol. Chem. 278, 43717–43727 (2003)

    Article  CAS  Google Scholar 

  26. Sambashivan, S., Liu, Y., Sawaya, M. R., Gingery, M. & Eisenberg, D. Amyloid-like fibrils of ribonuclease A with three-dimensional domain-swapped and native-like structure. Nature 437, 266–269 (2005)

    Article  ADS  CAS  Google Scholar 

  27. Thompson, M. J. et al. The 3D profile method for identifying fibril-forming segments of proteins. Proc. Natl Acad. Sci. USA 103, 4074–4078 (2006)

    Article  ADS  CAS  Google Scholar 

  28. Ivanova, M. I., Sawaya, M. R., Gingery, M., Attinger, A. & Eisenberg, D. An amyloid-forming segment of β2-microglobulin suggests a molecular model for the fibril. Proc. Natl Acad. Sci. USA 101, 10584–10589 (2004)

    Article  ADS  CAS  Google Scholar 

  29. Ivanova, M. I., Thompson, M. J. & Eisenberg, D. A systematic screen of β2-microglobulin and insulin for amyloid-like segments. Proc. Natl Acad. Sci. USA 103, 4079–4082 (2006)

    Article  ADS  CAS  Google Scholar 

  30. Fändrich, M. & Dobson, C. M. The behaviour of polyamino acids reveals an inverse side chain effect in amyloid structure formation. EMBO J. 21, 5682–5690 (2002)

    Article  Google Scholar 

  31. Harper, J. D. & Lansbury, P. T. Jr. Models of amyloid seeding in Alzheimer’s disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Annu. Rev. Biochem. 66, 385–407 (1997)

    Article  CAS  Google Scholar 

  32. Jarrett, J. T. & Lansbury, P. T. Jr. Amyloid fibril formation requires a chemically discriminating nucleation event: studies of an amyloidogenic sequence from the bacterial protein OsmB. Biochemistry 31, 12345–12352 (1992)

    Article  CAS  Google Scholar 

  33. Sikorski, P., Atkins, E. D. & Serpell, L. C. Structure and texture of fibrous crystals formed by Alzheimer’s Aβ(11–25) peptide fragment. Structure (Camb.) 11, 915–926 (2003)

    Article  CAS  Google Scholar 

  34. Makin, O. S., Atkins, E., Sikorski, P., Johansson, J. & Serpell, L. C. Molecular basis for amyloid fibril formation and stability. Proc. Natl Acad. Sci. USA 102, 315–320 (2005)

    Article  ADS  CAS  Google Scholar 

  35. Halverson, K., Fraser, P. E., Kirschner, D. A. & Lansbury, P. T. Jr. Molecular determinants of amyloid deposition in Alzheimer’s disease: conformational studies of synthetic β-protein fragments. Biochemistry 29, 2639–2644 (1990)

    Article  CAS  Google Scholar 

  36. Serpell, L. C. & Smith, J. M. Direct visualisation of the β-sheet structure of synthetic Alzheimer’s amyloid. J. Mol. Biol. 299, 225–231 (2000)

    Article  CAS  Google Scholar 

  37. Kajava, A. V., Baxa, U., Wickner, R. B. & Steven, A. C. A model for Ure2p prion filaments and other amyloids: the parallel superpleated β-structure. Proc. Natl Acad. Sci. USA 101, 7885–7890 (2004)

    Article  ADS  CAS  Google Scholar 

  38. Kajava, A. V., Aebi, U. & Steven, A. C. The parallel superpleated β-structure as a model for amyloid fibrils of human amylin. J. Mol. Biol. 348, 247–252 (2005)

    Article  CAS  Google Scholar 

  39. King, C. Y. & Diaz-Avalos, R. Protein-only transmission of three yeast prion strains. Nature 428, 319–323 (2004)

    Article  ADS  CAS  Google Scholar 

  40. Tanaka, M., Chien, P., Naber, N., Cooke, R. & Weissman, J. S. Conformational variations in an infectious protein determine prion strain differences. Nature 428, 323–328 (2004)

    Article  ADS  CAS  Google Scholar 

  41. Petkova, A. T. et al. Self-propagating, molecular-level polymorphism in Alzheimer’s β-amyloid fibrils. Science 307, 262–265 (2005)

    Article  ADS  CAS  Google Scholar 

  42. Chien, P. & Weissman, J. S. Conformational diversity in a yeast prion dictates its seeding specificity. Nature 410, 223–227 (2001)

    Article  ADS  CAS  Google Scholar 

  43. Jones, E. M. & Surewicz, W. K. Fibril conformation as the basis of species- and strain-dependent seeding specificity of mammalian prion amyloids. Cell 121, 63–72 (2005)

    Article  CAS  Google Scholar 

  44. Diaz-Avalos, R., King, C. Y., Wall, J., Simon, M. & Caspar, D. L. Strain-specific morphologies of yeast prion amyloid fibrils. Proc. Natl Acad. Sci. USA 102, 10165–10170 (2005)

    Article  ADS  CAS  Google Scholar 

  45. Tanaka, M., Collins, S. R., Toyama, B. H. & Weissman, J. S. The physical basis of how prion conformations determine strain phenotypes. Nature 442, 585–589 (2006)

    Article  ADS  CAS  Google Scholar 

  46. Lawrence, M. C. & Colman, P. M. Shape complementarity at protein/protein interfaces. J. Mol. Biol. 234, 946–950 (1993)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank D. L. D. Caspar, D. Anderson, D. Cascio, M. Gingery, M. Graf and K. Wüthrich for discussions, and the NSF, the NIH and the HHMI for support. S.A.S. was supported by an NSF IGERT training grant and M.I.A. by an NIH National Research Service Award. The 11 new structures shown in Fig. 2, and their structure factors, have been deposited in the Protein Data Bank with accession codes as follows: GNNQQNY form 2, 2OMM; NNQQ form 1, 2ONX; NNQQ form 2, 2OLX; VEALYL, 2OMQ; LYQLEN, 2OMP; VQIVYK, 2ON9; GGVVIA, 2ONV; MVGGVV form 1, 2ONA; MVGGVV form 2, 2OKZ; SSTSAA, 2ONW; SNQNNF, 2OL9. In addition, at http://www.doe-mbi.ucla.edu/~sawaya/chime/xtalpept/ we offer, for each microcrystal structure, coordinates of the asymmetric unit, the unit cell, many unit cells, and a pair of sheets. This site also offers Chime pages that illustrate the steric zipper, polar zippers, crystal packing and water exclusion.

Author Contributions M.R.S., S.S., R.N. and M.I.I contributed equally to this work.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, UCLA-DOE Institute of Genomics and Proteomics, Los Angeles, California 90095-1570, USA,

    Michael R. Sawaya, Shilpa Sambashivan, Rebecca Nelson, Magdalena I. Ivanova, Stuart A. Sievers, Marcin I. Apostol, Michael J. Thompson, Melinda Balbirnie, Jed J. W. Wiltzius, Heather T. McFarlane & David Eisenberg

  2. Department of Chemistry, Centre for Crystallographic Studies, University of Copenhagen, Universitetsparken 5, DK-2100 KBH, Denmark,

    Anders Ø. Madsen

  3. European Synchrotron Radiation Facility, BP 220, F-38043 Grenoble Cedex, France,

    Anders Ø. Madsen & Christian Riekel

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Correspondence to David Eisenberg.

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Competing interests

The 11 new structures shown in Fig. 2, and their structure factors, have been deposited in the Protein Data Bank with accession codes as follows: GNNQQNY form 2, 2OMM; NNQQ form 1, 2ONX; NNQQ form 2, 2OLX; VEALYL, 2OMQ; LYQLEN, 2OMP; VQIVYK, 2ON9; GGVVIA, 2ONV; MVGGVV form 1, 2ONA; MVGGVV form 2, 2OKZ; SSTSAA, 2ONW; SNQNNF, 2OL9. In addition, at http://www.doe-mbi.ucla.edu/˜sawaya/chime/xtalpept/ we offer, for each microcrystal structure, coordinates of the asymmetric unit, the unit cell, many unit cells, and a pair of sheets. This site also offers Chime pages that illustrate the steric zipper, polar zippers, crystal packing and water exclusion. Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

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Sawaya, M., Sambashivan, S., Nelson, R. et al. Atomic structures of amyloid cross-β spines reveal varied steric zippers. Nature 447, 453–457 (2007). https://doi.org/10.1038/nature05695

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