Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 392, Issue 3, Pages 689-700Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2009.07.031
Keywords
amyloid fibril; kappa-casein; polyphenol; (-)-epigallocatechin-3-gallate; EGCG
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Funding
- Australian Research Council
- National Health and Medical Research Council Peter Doherty Australian Biomedical Fellowship
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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-beta, alpha-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 RCM kappa-CN (reduced and carboxymethylated K-casein) and thereby protect pheochromocytoma-12 cells from RCM kappa-CN amyloid-induced toxicity. We found that EGCG potently inhibits in vitro fibril formation by RCM kappa-CN [the IC50 for 50 mu M RCM kappa-CN is 13 +/- 1 mu M]. Biophysical studies reveal that EGCG prevents RCM kappa-CN fibril formation by stabilising RCM kappa-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 RCM kappa-CN with high affinity by strong non-specific hydrophobic associations. Additional non-covalent pi-pi stacking interactions between the polyphenolic and aromatic residues common to the amyloidogenic sequence are also implicated. (C) 2009 Elsevier Ltd. All rights reserved.
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