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

Abstract

The sequence ₃₀₆VQIVYK₃₁₁ is an aggregation-prone region of the tau protein implicated in driving the assembly of tau into paired helical filaments. These filaments accumulate as intraneuronal neurofibrillary tangles in Alzheimer's disease and a range of tauopathies. Prolonged incubation of VQIVYK results in highly ordered fibrillar structures that give rise to unusually detailed and highly oriented X-ray fibre diffraction patterns. These mature fibrils provided the opportunity to use a novel integrative approach that combined X-ray fibre diffraction analysis with 3D contact point reconstruction atomic force microscopy (CPR-AFM) of individual filaments to determine molecular and supramolecular details. X-ray diffraction analysis resulted in a molecular model consistent with an X-ray crystallography structure, which could be further optimised to give rise to a highly twisted filamentous protofilament architecture. Analysis of individual fibril envelopes by CPR-AFM revealed a diverse polymorphous population with a major fibril morphology of apparently smooth, cylindrical fibrils, and morphological subpopulations of fibrils with clear left-handed twisting patterns, while X-ray diffraction suggests that the protofilament core structure remains consistent between the polymorphs. Here, we reveal that VQIVYK amyloid fibrils form a polymorphous amyloid population by assembly of highly ordered protofilaments. The combined approach provides novel molecular and supramolecular information regarding the structure of highly twisted amyloid fibrils.