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Structural identification of individual helical amyloid filaments by integration of cryo-electron microscopy-derived maps in comparative morphometric atomic force microscopy image analysis

Lutter, Liisa, Al-Hilaly, Youssra K., Serpell, Christopher J., Tuite, Mick F., Wischik, Claude M., Serpell, Louise C., Xue, Wei-Feng (2022) Structural identification of individual helical amyloid filaments by integration of cryo-electron microscopy-derived maps in comparative morphometric atomic force microscopy image analysis. Journal of Molecular Biology, . p. 167466. ISSN 0022-2836. (doi:10.1016/j.jmb.2022.167466) (KAR id:93220)

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https://doi.org/10.1016/j.jmb.2022.167466

Abstract

The presence of amyloid fibrils is a hallmark of more than 50 human disorders, including neurodegenerative diseases and systemic amyloidoses. A key unresolved challenge in understanding the involvement of amyloid in disease is to explain the relationship between individual structural polymorphs of amyloid fibrils, in potentially mixed populations, and the specific pathologies with which they are associated. Although cryo-electron microscopy (cryo-EM) and solid-state nuclear magnetic resonance (ssNMR) spectroscopy methods have been successfully employed in recent years to determine the structures of amyloid fibrils with high resolution detail, they rely on ensemble averaging of fibril structures in the entire sample or significant subpopulations. Here, we report a method for structural identification of individual fibril structures imaged by atomic force microscopy (AFM) by integration of high-resolution maps of amyloid fibrils determined by cryo-EM in comparative AFM image analysis. This approach was demonstrated using the hitherto structurally unresolved amyloid fibrils formed in vitro from a fragment of tau (297-391), termed ‘dGAE’. Our approach established unequivocally that dGAE amyloid fibrils bear no structural relationship to heparin-induced tau fibrils formed in vitro. Furthermore, our comparative analysis resulted in the prediction that dGAE fibrils are closely related structurally to the paired helical filaments (PHFs) isolated from Alzheimer’s disease (AD) brain tissue characterised by cryo-EM. These results show the utility of individual particle structural analysis using AFM, provide a workflow of how cryo-EM data can be incorporated into AFM image analysis and facilitate an integrated structural analysis of amyloid polymorphism.

Item Type: Article
DOI/Identification number: 10.1016/j.jmb.2022.167466
Uncontrolled keywords: atomic force microscopy; amyloid polymorphism ;structural biology; cryo-electron microscopy; image analysis; nano-morphometry tau; dGAE
Subjects: Q Science
Q Science > QP Physiology (Living systems) > QP506 Molecular biology
Q Science > QP Physiology (Living systems) > QP517 Biochemistry
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: Wei-Feng Xue
Date Deposited: 16 Feb 2022 15:31 UTC
Last Modified: 18 Feb 2022 17:30 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/93220 (The current URI for this page, for reference purposes)
Lutter, Liisa: https://orcid.org/0000-0001-7613-1953
Serpell, Christopher J.: https://orcid.org/0000-0002-2848-9077
Tuite, Mick F.: https://orcid.org/0000-0002-5214-540X
Xue, Wei-Feng: https://orcid.org/0000-0002-6504-0404
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