Molecular determinants of the interactions between SRC-1 and LXR/RXR heterodimers

Abstract

Liver X receptor (LXR)/retinoid X receptor (RXR) heterodimers have been shown to perform critical functions in cholesterol and lipid metabolism. Here, we have conducted a comparative analysis of the contributions of LXR and RXR binding to steroid receptor coactivator-1 (SRC-1), which contains three copies of the NR box. We demonstrated that the coactivator-binding surface of LXR, but not that of RXR, is critically important for physical and functional interactions with SRC-1, thereby confirming that RXR functions as an allosteric activator of SRC-1–LXR interaction. Notably, we identified NR box-2 and -3 as the essential binding targets for the SRC-1-induced stimulation of LXR transactivity, and observed the competitive in vitro binding of NR box-2 and -3 to LXR. Structured summary MINT- 7986678, MINT- 7986639, MINT- 7986700, MINT- 7986720, MINT- 7986736, MINT- 7986760, MINT- 7986787: LXR (uniprotkb: Q13133) physically interacts (MI: 0915) with SRC1 (uniprotkb: Q15788) and RXR (uniprotkb: P19793) by pull down (MI: 0096) MINT- 7986596, MINT- 7986621: SRC1 (uniprotkb: Q15788) physically interacts (MI: 0915) with LXR (uniprotkb: Q13133) by pull down (MI: 0096) MINT- 7986555, MINT- 7986575: LXR (uniprotkb: Q13133) physically interacts (MI: 0915) with SRC1 (uniprotkb: Q15788) by two hybrid (MI: 0018) MINT- 7986808, MINT- 7986907, MINT- 7986890: SRC1 (uniprotkb: Q15788) binds (MI: 0407) to LXR (uniprotkb: Q13133) by pull down (MI: 0096) MINT- 7986822, MINT- 7986848, MINT- 7986865: SRC1 (uniprotkb: Q15788) binds (MI: 0407) to RXR (uniprotkb: P19793) by pull down (MI: 0096)