Phosphorylation of PPAR? Affects the Collective Motions of the PPAR?-RXR?-DNA Complex.

ABSTRACT: Peroxisome-proliferator activated receptor-? (PPAR?) is a nuclear hormone receptor that forms a heterodimeric complex with retinoid X receptor-? (RXR?) to regulate transcription of genes involved in fatty acid storage and glucose metabolism. PPAR? is a target for pharmaceutical intervention in type 2 diabetes, and insight into interactions between PPAR?, RXR?, and DNA is of interest in understanding the function and regulation of this complex. Phosphorylation of PPAR? by cyclin-dependent kinase 5 (Cdk5) has been shown to dysregulate the expression of metabolic regulation genes, an effect that is counteracted by PPAR? ligands. We applied molecular dynamics (MD) simulations to study the relationship between the ligand-binding domains of PPAR? and RXR? with their respective DNA-binding domains. Our results reveal that phosphorylation alters collective motions within the PPAR?-RXR? complex that affect the LBD-LBD dimerization interface and the AF-2 coactivator binding region of PPAR?.

SUBMITTER: Lemkul JA 

PROVIDER: S-EPMC4425662 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature