Amyloid fibrils formed from different proteins, each associated with a particular disease, contain a common cross-beta 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 beta-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-beta and tau proteins, the PrP prion protein, insulin, islet amyloid polypeptide (IAPP), lysozyme, myoglobin, alpha-synuclein and beta(2)-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.

Numerous soluble proteins convert to insoluble amyloid-like fibrils having 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, which here reveal the atomic structure of the cross-β spine. It is a double β-sheet, with each sheet formed from parallel segments stacked in-register. Sidechains 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 via stacks of both backbone and sidechain hydrogen bonds. The structure illuminates the stability of amyloid fibrils, their self-seeding characteristic, and their tendency to form polymorphic structures.Four decades of research have established that amyloid-like fibrils of different proteins have a common structural 'cross-β' spine 1 . In 1959 Cohen and Calkins 2 observed elongated, unbranched fibrils in electron micrographs of diseased tissues, and in 1968 Glenner and Eanes 3 discovered that the fibrils exhibit an X-ray diffraction signature known as the cross-β pattern. This pattern shows 4 that the strongest repeating feature of the fibril is a set of β-sheets that are parallel to the fibril axis with their strands perpendicular to this axis. The hypothesis of a common molecular organization was supported by the finding 5 that amyloid fibrils from 6 different proteins, each associated with its own clinical syndrome, showed similar cross-β diffraction patterns. The degree of similarity pointed to 'a common core molecular structure.'Revealing the atomic details of this cross-β spine has been impeded by the limited order of fibrils isolated from diseased tissues, infected cells, and in vitro conversions of proteins to fibrils. There is also evidence for a diversity of crystalline and fibril structures 6-8 . Nevertheless, an arsenal of biophysical tools has defined important features. These tools include solid-state NMR 9-11 , model-building constrained by X-ray fiber and powder diffraction 6,7,12,13 , site-directed spin labeling 14,15 , cryo-electron microscopy 16,17 , and proline-scanning mutagenesis 18 . Despite numerous models suggested by these studies, until now no refined, fully objective atomic model has been available for the common spine structure.Correspondence and requests for materials should be addressed to D.E. (david@mbi.ucla.edu). The structures of GNNQQNY and NNQQNY have been deposited in the Protein Data Bank with accession codes 1yjp and 1yjo, respectively.. Competing Interests StatementThe authors declare that they have no competing financial interests.Supplementary Information accompanies the paper on www.nature.com/nature. We selected the yeast protein Sup35 for X-ray diffraction analy...

The SHADE web server estimates anisotropic displacement parameters for hydrogen atoms by combining a rigid-body analysis of the non-hydrogen-atom anisotropic displacement parameters (ADPs) with a contribution from internal atomic motion. The contributions from internal mean square displacements are based on a previously compiled database derived from analysis of neutron diffraction experiments. The estimated hydrogen-atom ADPs can be used as fixed parameters in advanced applications of high-resolution X-ray diffraction, such as electron density studies using multipole modelling. The resulting electron density models have been shown to be in excellent agreement with reference models based on atomic motion derived from neutron diffraction experiments.