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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.

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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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