A molecular model of the amyloid fibril

We have investigated the ultrastructure of the homozygous amyloid fibrils from the vitreous humour of patients with Met30 familial amyloidotic polyneuropathy (FAP) by high-resolution electron microscopy and X-ray diffraction using synchrotron radiation. Image reconstruction of thin sections of Met30 FAP fibrils shows that they are composed of four parallel protofilaments, 50-60 Å in diameter, arranged in a square around a hollow centre. The X-ray diffraction patterns are consistent with the presence in the protofilaments of a repeating unit of 24 ß-strands forming a continuous ß-sheet extended along the fibre axis, with the ß-strands perpendicular to the axis. We have characterized this repeat unit as one turn of a ß-sheet helix. This newly-described helix reconciles the classical cross-ß structure of amyloid with the twisted ß-sheet that is known to be the most stable form of the structure. All four ß-sheets composing the protofilament twist around a single helical axis which is coincident with the axis of the protofilament. Other amyloid diffraction patterns are similar to that of FAP, suggesting that the ß-sheet helix may be the generic core structure of amyloid.