The supramolecular architecture of amyloid fibrils formed by a human tau-derived hexapeptide VQIVYK
Year: 2025
Type: article
Abstract: 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.
Source: Nanoscale
DOI: 10.1039/d5nr04317d
Institutions: University of Sussex, University of Kent, Mustansiriyah University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: G1052723817, G1120406305, The suprastructure-function relationship between amyloid assemblies and their toxic and infectious potentials, DTP 2018-19 University of Kent, G4713601911, The suprastructure-function relationship between amyloid assemblies and their toxic and infectious potentials, G8646822034, Creating in vitro assembled protein nano-fibrils that mimic polymorphous disease-relevant amyloid structures formed in vivo, G977868684
OpenAlex ID: W7117354157