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Type: Journal article
Title: (-)-Epigallocatechin-3-gallate (EGCG) Maintains k-Casein in its pre-fibrillar state without redirecting its aggregation pathway
Author: Hudson, S.
Ecroyd, H.
Dehle, F.
Musgrave, I.
Carver, J.
Citation: Journal of Molecular Biology, 2009; 392(3):689-700
Publisher: Academic Press Ltd Elsevier Science Ltd
Issue Date: 2009
ISSN: 0022-2836
Statement of
Sean A. Hudson, Heath Ecroyd, Francis C. Dehle, Ian F. Musgrave and John A. Carver
Abstract: The polyphenol (−)-epigallocatechin-3-gallate (EGCG) has recently attracted much research interest in the field of protein-misfolding diseases because of its potent anti-amyloid activity against amyloid-β, α-synuclein and huntingtin, the amyloid-fibril-forming proteins involved in Alzheimer's, Parkinson's and Huntington's diseases, respectively. EGCG redirects the aggregation of these polypeptides to a disordered off-folding pathway that results in the formation of non-toxic amorphous aggregates. Whether this anti-fibril activity is specific to these disease-related target proteins or is more generic remains to be established. In addition, the mechanism by which EGCG exerts its effects, as with all anti-amyloidogenic polyphenols, remains unclear. To address these aspects, we have investigated the ability of EGCG to inhibit amyloidogenesis of the generic model fibril-forming protein RCMκ-CN (reduced and carboxymethylated κ-casein) and thereby protect pheochromocytoma-12 cells from RCMκ-CN amyloid-induced toxicity. We found that EGCG potently inhibits in vitro fibril formation by RCMκ-CN [the IC50 for 50 μM RCMκ-CN is 13 ± 1 μM]. Biophysical studies reveal that EGCG prevents RCMκ-CN fibril formation by stabilising RCMκ-CN in its native-like state rather than by redirecting its aggregation to the disordered, amorphous aggregation pathway. Thus, while it appears that EGCG is a generic inhibitor of amyloid-fibril formation, the mechanism by which it achieves this inhibition is specific to the target fibril-forming polypeptide. It is proposed that EGCG is directed to the amyloidogenic sheet–turn–sheet motif of monomeric RCMκ-CN with high affinity by strong non-specific hydrophobic associations. Additional non-covalent π–π stacking interactions between the polyphenolic and aromatic residues common to the amyloidogenic sequence are also implicated.
Keywords: amyloid fibril; κ-casein; polyphenol; (−)-epigallocatechin-3-gallate; EGCG
Description: Copyright © 2009 Elsevier B.V. All rights reserved. ScienceDirect® is a registered trademark of Elsevier B.V.
RMID: 0020092324
DOI: 10.1016/j.jmb.2009.07.031
Appears in Collections:Chemistry and Physics publications

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