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

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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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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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Competing interests

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 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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