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Structure of the cross-β spine of amyloid-like fibrils

Abstract

Numerous soluble proteins convert to insoluble amyloid-like fibrils that have common properties. Amyloid fibrils are associated with fatal diseases such as Alzheimer's, and amyloid-like fibrils can be formed in vitro. For the yeast protein Sup35, conversion to amyloid-like fibrils is associated with a transmissible infection akin to that caused by mammalian prions. A seven-residue peptide segment from Sup35 forms amyloid-like fibrils and closely related microcrystals, from which we have determined the atomic structure of the cross-β spine. It is a double β-sheet, with each sheet formed from parallel segments stacked in register. Side chains protruding from the two sheets form a dry, tightly self-complementing steric zipper, bonding the sheets. Within each sheet, every segment is bound to its two neighbouring segments through stacks of both backbone and side-chain hydrogen bonds. The structure illuminates the stability of amyloid fibrils, their self-seeding characteristic and their tendency to form polymorphic structures.

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Figure 1: The NNQQNY microcrystal used for X-ray diffraction data collection, held to the tip of a glass capillary by cryoprotectant (50% ethylene glycol/water).
Figure 2: Structure of GNNQQNY.
Figure 3: A conjectural plot of the free energy, G , for conversion of monomeric GNNQQNY, M , to the aggregated state, Mn.

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Acknowledgements

We thank the late Carl Branden for initiating the UCLA–ESRF collaboration; D. L. D. Caspar, R. Diaz-Avalos, Y. Fujiyoshi, R. G. Griffin, S. Larsen, K. Mitsuoka, P. W. Stevens, J.-H. Her and T. O. Yeates for discussions; S. Horvath for peptide synthesis; and NIH, NSF, HHMI and USPHS National Research Service Award for support.

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Correspondence to David Eisenberg.

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The structures of GNNQQNY and NNQQNY have been deposited in the Protein Data Bank with accession codes 1yjp and 1yjo, respectively. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Notes

This contains three supplementary figures, one supplementary table, and a description of structure-based energetics calculations. Figure S1 shows the Harker section of an anomalous difference Patterson map used in structure determination. Figure S2 compares the cross beta X-ray diffraction patterns of GNNQQNY fibrils and crystals. Figure S3 shows the structure of NNQQNY. Table S1 lists the dihedral angles of the GNNQQNY structure. (DOC 2111 kb)

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Nelson, R., Sawaya, M., Balbirnie, M. et al. Structure of the cross-β spine of amyloid-like fibrils. Nature 435, 773–778 (2005). https://doi.org/10.1038/nature03680

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