Aggregation Kinetics and Filament Structure of a Tau Fragment Are Influenced by the Sulfation Pattern of the Cofactor Heparin

Townsend, David and Fullwood, Nigel and Yates, Edwin and Middleton, David (2020) Aggregation Kinetics and Filament Structure of a Tau Fragment Are Influenced by the Sulfation Pattern of the Cofactor Heparin. Biochemistry. ISSN 0006-2960

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Abstract

A pathological signature of Alzheimer’s disease (AD) is the formation of neurofibrillary tangles comprising filamentous aggregates of the microtubule associated protein tau. Tau self-assembly is accelerated by polyanions including heparin, an analogue of heparan sulfate. Tau filaments colocalize with heparan sulfate proteoglycans (HSPGs) in vivo, and HSPGs may also assist the transcellular propagation of tau aggregates. Here, we investigate the role of the sulfate moieties of heparin in the aggregation of a recombinant tau fragment Δtau187, comprising residues 255–441 of the C-terminal microtubule-binding domain. The effects that the selective removal of the N-, 2-O-, and 6-O-sulfate groups from heparin have on the kinetics of tau aggregation, aggregate morphology, and protein structure and dynamics were examined. Aggregation kinetics monitored by thioflavin T (ThT) fluorescence revealed that aggregation is considerably slower in the presence of 2-O-desulfated heparin than with N- or 6-O-desulfated heparin. Transmission electron microscopy revealed that tau filaments induced by 2-O-desulfated heparin were more slender than filaments formed in the presence of intact heparin or 6-O-desulfated heparin. The 2-O-desulfated heparin-induced filaments had more extensive regions of flexibility than the other filaments, according to circular dichroism and solid-state NMR spectroscopy. These results indicate that the sulfation pattern of heparin regulates tau aggregation, not purely though electrostatic forces but also through conformational perturbations of heparin when the 2-O-sulfate is removed. These findings may have implications for the progression of AD, as the sulfation pattern of GAGs is known to change during the aging process, which is the main risk factor for the disease.

Item Type:
Journal Article
Journal or Publication Title:
Biochemistry
Additional Information:
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biochemistry, copyright ©2020 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.biochem.0c00443
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1303
Subjects:
ID Code:
148021
Deposited By:
Deposited On:
09 Oct 2020 12:45
Refereed?:
Yes
Published?:
Published
Last Modified:
31 Oct 2020 07:21