SYNCHROTRON X-RAY STUDIES SUGGEST THAT THE CORE OF THE TRANSTHYRETIN AMYLOID FIBRIL IS A CONTINUOUS BETA-SHEET HELIX

Background: Amyloid diseases, which include Alzheimer's disease and th e transmissible spongiform encephalopathies, are characterized by the extracellular deposition of abnormal protein fibrils derived from solu ble precursor proteins. Although different precursors seem to generate similar fibrils, no adequate molecular structure of amyloid fibrils h as been produced using modern techniques. Knowledge of the fibril stru cture is essential to understanding the molecular mechanism of amyloid formation and could lead to the development of agents to inhibit or r everse the process. Results: The structure of amyloid fibrils from pat ients with familial amyloidotic polyneuropathy (FAP), which are derive d from transthyretin (TTR) variants, has been investigated by fibre di ffraction methods using synchrotron radiation. For the first time a si gnificant high-angle diffraction pattern has been observed showing mer idional reflections out to 2 Angstrom resolution. This pattern was ful ly consistent with the previously reported cross-beta structure for th e fibril, but also reveals a new large scale fibre repeat of 115 Angst rom. We interpret this pattern as that of a repeating unit of 24 beta strands, which form a complete helical turn of beta sheet about an axi s parallel to the fibre axis. This structure has not been observed pre viously. We have built a model of the protofilament of the FAP amyloid fibril based on this interpretation, composed of four beta sheets rel ated 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 co nsisting of beta sheets extended in regular helical twists along the l ength of the fibre. This implies that the polypeptide chains in the fi bres are hydrogen-bonded together along the entire length of the fibre s, thereby accounting for their great stability. The proposed structur e of the FAP fibril requires a TTR building block that is structurally different from the native tetramer. This is likely to be either a mon omer or dimer with reorganized or truncated beta sheets, suggesting th at amyloid formation may require significant structural change in prec ursor proteins.