The Crystal Structure of the Green Tea Polyphenol (−)-Epigallocatechin Gallate−Transthyretin Complex Reveals a Novel Binding Site Distinct from the Thyroxine Binding Site,

Abstract

Amyloid fibril formation is associated with protein misfolding disorders, including neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. Familial amyloid polyneuropathy (FAP) is a hereditary disease caused by a point mutation of the human plasma protein, transthyretin (TTR), which binds and transports thyroxine (T(4)). TTR variants contribute to the pathogenesis of amyloidosis by forming amyloid fibrils in the extracellular environment. A recent report showed that epigallocatechin 3-gallate (EGCG), the major polyphenol component of green tea, binds to TTR and suppresses TTR amyloid fibril formation. However, structural analysis of EGCG binding to TTR has not yet been conducted. Here we first investigated the crystal structure of the EGCG-V30M TTR complex and found novel binding sites distinct from the thyroxine binding site, suggesting that EGCG has a mode of action different from those of previous chemical compounds that were shown to bind and stabilize the TTR tetramer structure. Furthermore, EGCG induced the oligomerization and monomer suppression in the cellular system of clinically reported TTR variants. Taken together, these findings suggest the possibility that EGCG may be a candidate compound for FAP therapy.

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

“…S-11). In conclusion, these and previously published results point to EGCG as a generic binder [34][35][36][37][38][39][40][41][42] and modulator 41,42 of protein structure.…”

Natural polyphenols inhibit different steps of the process of transthyretin (TTR) amyloid fibril formation

“…Concerning EGCG, it does not compete with T 4 for the binding to TTR [13] therefore the stabilization effect of EGCG on TTR is independent from the stabilization effect of T 4 and additionally strengthens the effect of T 4 [21]. Furthermore, the characterization of the EGCG-TTR V30M complex revealed that EGCG binds at the surface of TTR molecule, in a region involving amino acid residues at the interface of both dimmers, promoting tetramer stabilization [21].…”

The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies

“…3), further indicated that EGCG directly bound and stabilised TTR tetramer in vitro, and induced TTR oligomerisation in cells 34 . The pharmaceutical mechanism of EGCG curing of yeast prions [PSI] could be via stabilisation of the native prion domain Sup35 as well 35 .…”