Tight Binding of Natural Polyphenols to the Intrinsically Disordered Mammalian High Mobility Group Protein At-Hook 2

Abstract

The mammalian high mobility group protein AT-hook 2 (HMGA2) is an intrinsically disordered protein (IDP) that specifically recognizes the minor-groove of AT-rich DNA sequence. It works as a multifunctional DNA-binding protein and plays important roles in tumorigenesis and adipogenesis. Previous studies showed that HMGA2 is a potential therapeutic target of anticancer and anti-obesity drugs by inhibiting its DNA-binding activities. In this study, we found that several natural polyphenols, such as aurintricarboxylic acid, gallic acid, ellagic acid, and (−)-epigallocatechin gallate (EGCG) tightly bind to HMGA2 and, as a result, strongly inhibit HMGA2 binding to AT-rich DNA sequences. Since these polyphenols can inhibit adipogenesis in vitro and in animal models, our results suggest that their anti-obesity activities may stem from their inhibition of HMGA2-DNA interactions. Because polyphenols are naturally occurring chemical compounds enriched in vegetables and fruits, our discovery strongly support that vegetables and fruits are natural remedies to treat obesity.