The molecular structure of the amyloid fibril has remained elusive because of the difficulty of growing well diffracting crystals. By using a sequence-designed polypeptide, we have produced crystals of an amyloid fiber. These crystals diffract to high resolution (1 Å) by electron and x-ray diffraction, enabling us to determine a detailed structure for amyloid. The structure reveals that the polypeptides form fibrous crystals composed of antiparallel ␤-sheets in a cross-␤ arrangement, characteristic of all amyloid fibers, and allows us to determine the side-chain packing within an amyloid fiber. The antiparallel ␤-sheets are zipped together by means of -bonding between adjacent phenylalanine rings and salt-bridges between charge pairs (glutamic acid-lysine), thus controlling and stabilizing the structure. These interactions are likely to be important in the formation and stability of other amyloid fibrils.x-ray diffraction ͉ side-chain packing ͉ structure ͉ -bonding ͉ ␤-sheet interaction

Alzheimer's disease and Creutzfeldt–Jakob disease are the best‐known examples of a group of diseases known as the amyloidoses. They are characterized by the extracellular deposition of toxic, insoluble amyloid fibrils. Knowledge of the structure of these fibrils is essential for understanding the process of pathology of the amyloidoses and for the rational design of drugs to inhibit or reverse amyloid formation. Structural models have been built using information from a wide variety of techniques, including X‐ray diffraction, electron microscopy, solid state NMR and EPR. Recent advances have been made in understanding the architecture of the amyloid fibril. Here, we describe and compare postulated structural models for the mature amyloid fibril and discuss how the ordered structure of amyloid contributes to its stability.

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Fibrillar inclusions are a characteristic feature of the neuropathology found in the a-synucleinopathies such as Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Familial forms of asynucleinopathies have also been linked with missense mutations or gene multiplications that result in higher protein expression levels. In order to form these fibrils, the protein, a-synuclein (a-syn), must undergo a process of self-assembly in which its native state is converted from a disordered conformer into a b-sheet-dominated form. Here, we have developed a novel polypeptide property calculator to locate and quantify relative propensities for b-strand structure in the sequence of a-syn. The output of the algorithm, in the form of a simple x-y plot, was found to correlate very well with the location of the b-sheet core in a-syn fibrils. In particular, the plot features three peaks, the largest of which is completely absent for the nonfibrillogenic protein, b-syn. We also report similar significant correlations for the Alzheimer's diseaserelated proteins, Ab and tau. A substantial region of a-syn is also of converting from its disordered conformation into a long amphipathic a-helical protein. We have developed the aforementioned algorithm to locate and quantify the a-helical hydrophobic moment in the amino acid sequence of a-syn. As before, the output of the algorithm, in the form of a simple x-y plot, was found to correlate very well with the location of a-helical structure in membrane bilayer-associated a-syn.

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