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Phosphorylation of PPARγ Affects the Collective Motions of the PPARγ-RXRα-DNA Complex

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  • Justin A Lemkul
  • Stephanie N Lewis
  • Josep Bassaganya-Riera
  • David R Bevan

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.

Suggested Citation

  • Justin A Lemkul & Stephanie N Lewis & Josep Bassaganya-Riera & David R Bevan, 2015. "Phosphorylation of PPARγ Affects the Collective Motions of the PPARγ-RXRα-DNA Complex," PLOS ONE, Public Library of Science, vol. 10(5), pages 1-21, May.
    • Handle: RePEc:plo:pone00:0123984
    DOI: 10.1371/journal.pone.0123984
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    1. Robert T. Nolte & G. Bruce Wisely & Stefan Westin & Jeffery E. Cobb & Millard H. Lambert & Riki Kurokawa & Michael G. Rosenfeld & Timothy M. Willson & Christopher K. Glass & Michael V. Milburn, 1998. "Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ," Nature, Nature, vol. 395(6698), pages 137-143, September.
    2. Dalei Shao & Shamina M. Rangwala & Shannon T. Bailey & Samuel L. Krakow & Mauricio J. Reginato & Mitchell A. Lazar, 1998. "Interdomain communication regulating ligand binding by PPAR-γ," Nature, Nature, vol. 396(6709), pages 377-380, November.
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