Abstract
Peroxisome-proliferator activated receptor-γ (PPARγ) is a nuclear hormone receptor that forms a heterodimeric complex with retinoid X receptor-α (RXRα) to regulate transcription of genes involved in fatty acid storage and glucose metabolism. PPARγ is a target for pharmaceutical intervention in type 2 diabetes, and insight into interactions between PPARγ, RXRα, and DNA is of interest in understanding the function and regulation of this complex. Phosphorylation of PPARγ by cyclin-dependent kinase 5 (Cdk5) has been shown to dysregulate the expression of metabolic regulation genes, an effect that is counteracted by PPARγ ligands. We applied molecular dynamics (MD) simulations to study the relationship between the ligand-binding domains of PPARγ and RXRα with their respective DNA-binding domains. Our results reveal that phosphorylation alters collective motions within the PPARγ-RXRα complex that affect the LBD-LBD dimerization interface and the AF-2 coactivator binding region of PPARγ.
Highlights
Peroxisome-proliferator activated receptor-γ (PPARγ) is a transcription factor within the nuclear hormone receptor family that forms a heterodimeric complex with retinoid X receptor-α (RXRα) to bind coactivator proteins that recruit additional transcription factors to PPAR response element (PPRE) sequences, which are generally located in enhancer regions far upstream from the target genes [1,2]
PPARγ is a transcription factor within the nuclear hormone receptor family that forms a heterodimeric complex with RXRα to bind coactivator proteins that recruit additional transcription factors to PPRE sequences, which are generally located in enhancer regions far upstream from the target genes [1,2]
All complexes in our simulations contained PPARγ, RXRα, and DNA, with differences among the complexes consisting of phosphorylation state of Ser245 and presence or absence of ligands or coactivator peptides
Summary
PPARγ is a transcription factor within the nuclear hormone receptor family that forms a heterodimeric complex with RXRα to bind coactivator proteins that recruit additional transcription factors to PPRE sequences, which are generally located in enhancer regions far upstream from the target genes [1,2]. PPARγ has a structure that is typical of nuclear hormone receptors, containing an N-terminal A/B domain of unknown structure followed by two principally αhelical domains, a 12-helix ligand-binding domain (LBD) and a zinc-finger DNA-binding domain (DBD). There are two isoforms of PPARγ (PPARγ1 and PPARγ2), with PPARγ2 containing an N-terminal extension of 28 amino acids. The two isoforms are otherwise identical throughout the LBD and DBD. The LBD of PPARγ serves to bind endogenous ligands, and to dimerize with RXRα and bind
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