Abstract
Liver X receptor alpha (LXRα) is crucial for the maintenance of lipid and cholesterol homeostasis. Ligand binding and dimerization with retinoid X receptor (RXR) or peroxisome proliferator-activated receptor (PPAR) is required for forming active DNA binding complexes leading to gene regulation. Structure based prediction and solvent accessibility of LXRα LBD shows that residues H383, E387, H390, L414, and R415 which are located in helices 9 and 10 may be critical for mediating protein-protein interactions. In this study, LXRα interface residues were individually mutated to determine their effects on ligand binding, protein-protein association, subcellular localization, and transactivation activity. LXRα L414R and R415A lacked binding to T-0901317, but retained binding to 25-Hydroxycholesterol. In vitro assay and a cell based assay demonstrated that LXRα L414R was specifically impaired for interactions with RXRα but not PPARα suggesting that charge reversal at the interface provides selectivity to LXRα dimerization. Furthermore, binding of LXRα L414R or R415A with PPARα exhibited minimal conformational changes in the dimer secondary structure. Interestingly, all LXRα mutants exhibited lower levels of ligand dependent luciferase activity driven by the SREBP-1c or ApoA1 promoter. Taken together, our data demonstrates that intact hydrophobic interactions and salt bridges at the interface mediate efficient ligand-dependent transactivation activities.
Highlights
Nuclear hormone receptors PPARα and LXRα are ligand activated transcription factors that are activated by fatty acids and oxysterols respectively [1, 2]
These receptors act as sensors of elevated levels of fatty acids and cholesterol derivatives via the receptor ligand binding domain (LBD) to regulate the expression of genes involved in controlling cholesterol and lipid metabolism [3, 4]
Our results revealed that LXRα L414 is required for the formation of LXRα-RXRα complexes
Summary
Nuclear hormone receptors PPARα and LXRα are ligand activated transcription factors that are activated by fatty acids and oxysterols respectively [1, 2] These receptors act as sensors of elevated levels of fatty acids and cholesterol derivatives via the receptor ligand binding domain (LBD) to regulate the expression of genes involved in controlling cholesterol and lipid metabolism [3, 4]. Due to the crucial roles of these receptors in maintaining constant level of lipids in cells, PPARα and LXRα represent interesting targets for the development of pharmacological compounds in the treatment of metabolic disorders [6]. Drugs targeting these receptors exhibit anti-atherogenic, anti-inflammatory, and anti-diabetic effects.
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