Synchrotron X-ray studies suggest that the core of the transthyretin amyloid fibril is a continuous ß-sheet helix

Background: Amyloid diseases, which include Alzheimer's disease and the transmissible spongiform encephalopathies, are characterized by the extracellular deposition of abnormal protein fibrils derived from soluble precursor proteins. Although different precursors seem to generate similar fibrils, no adequate molecular structure of amyloid fibrils has been produced using modern techniques. Knowledge of the fibril structure is essential to understanding the molecular mechanism of amyloid formation and could lead to the development of agents to inhibit or reverse the process. Results: The structure of amyloid fibrils from patients with familial amyloidotic polyneuropathy (FAP), which are derived from transthyretin (TTR) variants, has been investigated by fibre diffraction methods using synchrotron radiation. For the first time a significant high-angle diffraction pattern has been observed showing meridional reflections out to 2 Å resolution. This pattern was fully consistent with the previously reported cross-ß structure for the fibril, but also reveals a new large scale fibre repeat of 115 Å. We interpret this pattern as that of a repeating unit of 24 ß strands, which form a complete helical turn of ß sheet about an axis parallel to the fibre axis. This structure has not been observed previously. We have built a model of the protofilament of the FAP amyloid fibril based on this interpretation, composed of four ß sheets related by a single helix axis coincident with the fibre axis, and shown that it is consistent with the observed X-ray data. Conclusions: This work suggests that amyloid fibrils have a novel molecular structure consisting of ß sheets extended in regular helical twists along the length of the fibre. This implies that the polypeptide chains in the fibers are hydrogen-bonded together along the entire length of the fibers, thereby accounting for their great stability. The proposed structure of the FAP fibril requires a TTR building block that is structurally different from the native tetramer. This is likely to be either a monomer or dimer with reorganized or truncated ß sheets, suggesting that amyloid formation may require significant structural change in precursor proteins.