The architecture of amyloid fibrils formed by a human tau-derived hexapeptide VQIVYK

Abstract The sequence VQIVYK is an aggregation prone region of the tau protein implicated in driving assembly of tau into paired helical filaments. These filaments accumulate as intraneuronal neurofibrillary tangles in Alzheimers disease and a range of tauopathies. Here, we demonstrate that VQIVYK forms highly ordered fibrillar samples after prolonged incubation at room temperature. Remarkably, aligned fibre bundles give rise to unusually detailed and highly oriented X-ray fibre diffraction patterns. Analysis of these patterns provide a model of the core protofilament structure that satisfies the experimental diffraction data. This structural model is consistent with data from X-ray crystallography of microcrystals and conforms to the cross-beta architecture that defines amyloid, but diffraction data analysis shows a highly twisted filamentous protofilament architecture. Analysis of individual fibril envelopes by 3D contact point reconstruction atomic force microscopy reveals a diverse polymorphous population with a major fibril morphology of apparent cylindrical fibrils, and morphological subpopulations of fibrils with clear left-hand twisting patterns, despite the commonality of the core structure indicated by the detailed diffraction pattern. Together, these data suggest that VQIVYK amyloid fibrils form a polymorphous amyloid population by assembly of highly ordered protofilaments and provides molecular information regarding amyloid fibril twist. Competing Interest Statement The authors have declared no competing interest.