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  • J. Biol. Chem.-2018-Townsend-jbc.RA118.002038

    Rights statement: This research was originally published in the Journal of Biological Chemistry. David Townsend, Eleri Hughes, Geoffrey Akien, Katie L. Stewart, Sheena E. Radford, David Rochester and David A. Middleton Epigallocatechin-3-gallate remodels apolipoprotein A-I amyloid fibrils into soluble oligomers in the presence of heparin. J. Biol. Chem. 2018; 293:12877. © 2018 Townsend et al. Author's Choice—Final version open access under the terms of the Creative Commons CC-BY license.

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    Available under license: CC BY-NC: Creative Commons Attribution-NonCommercial 4.0 International License

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Epigallocatechin-3-gallate remodels apolipoprotein A-I amyloid fibrils into soluble oligomers in the presence of heparin

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<mark>Journal publication date</mark>17/08/2018
<mark>Journal</mark>Journal of Biological Chemistry
Issue number33
Volume293
Number of pages17
Pages (from-to)12877-12893
Publication StatusPublished
Early online date31/05/18
<mark>Original language</mark>English

Abstract

Amyloid deposits of wild-type apolipoprotein A-I (apoA-I), the main protein component of high-density lipoprotein, accumulate in atherosclerotic plaques where they may contribute to coronary artery disease by increasing plaque burden and instability. Using CD analysis, solid-state NMR spectroscopy, and transmission EM, we report here a surprising cooperative effect of heparin and the green tea polyphenol (-)- epigallocatechin-3-gallate (EGCG), a known inhibitor and modulator of amyloid formation, on apoA-I fibrils. We found that heparin, a proxy for glycosaminoglycan (GAG) polysaccharides that co-localize ubiquitously with amyloid in vivo, accelerates the rate of apoA-I formation from monomeric protein and associates with insoluble fibrils. Mature, insoluble apoA-I fibrils bound EGCG (KD = 30 ± 3 μM; Bmax = 40 ± 3 μM), but EGCG did not alter the kinetics of apoA-I amyloid assembly from monomer in the presence or absence of heparin. EGCG selectively increased the mobility of specific backbone and side-chain sites of apoA-I fibrils formed in the absence of heparin, but the fibrils largely retained their original morphology and remained insoluble. By contrast, fibrils formed in the presence of heparin were mobilized extensively by the addition of equimolar EGCG, and the fibrils were remodeled into soluble 20-nm-diameter oligomers with a largely α-helical structure that were nontoxic to human umbilical artery endothelial cells. These results argue for a protective effect of EGCG on apoA-I amyloid associated with atherosclerosis and suggest that EGCG-induced remodeling of amyloid may be tightly regulated by GAGs and other amyloid co-factors in vivo, depending on EGCG bioavailability.

Bibliographic note

This research was originally published in the Journal of Biological Chemistry. David Townsend, Eleri Hughes, Geoffrey Akien, Katie L. Stewart, Sheena E. Radford, David Rochester and David A. Middleton Epigallocatechin-3-gallate remodels apolipoprotein A-I amyloid fibrils into soluble oligomers in the presence of heparin. J. Biol. Chem. 2018; 293:12877. © 2018 Townsend et al. Author's Choice—Final version open access under the terms of the Creative Commons CC-BY license.