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Solution Structures of PPARγ2/RXRα Complexes

Judit Osz1, Maxim V Pethoukhov, Serena Sirigu

  • 1Department of Integrative Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de Recherche Scientifique (CNRS) UMR 7104, Institut National de Santé et de Recherche Médicale (INSERM) U964, Université de Strasbourg, 67404 Illkirch, France.

PPAR Research
|January 16, 2013
PubMed

Insights

Peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR) form a heterodimer crucial for gene regulation. Structural studies reveal DNA binding induces asymmetry, affecting coactivator TIF2 binding.

Area of Science:

  • Molecular Biology
  • Structural Biology
  • Endocrinology

Background:

  • Peroxisome proliferator-activated receptor gamma (PPARγ) is vital for glucose homeostasis and insulin sensitivity.
  • PPARγ requires heterodimerization with retinoid X receptor (RXR) to bind DNA and regulate gene networks.
  • Coactivators like p160 and PGC-1α interact with the PPARγ/RXR complex to modulate gene expression.

Purpose of the Study:

  • To elucidate the structural basis of coactivator recognition by the PPARγ/RXRα heterodimer.
  • To determine the topological organization of PPARγ/RXRα complexes bound to DNA and coactivators.
  • To understand how DNA influences the structure and function of the PPARγ/RXRα heterodimer.

Main Methods:

  • Small-angle X-ray scattering (SAXS) was employed to study the structural properties of the PPARγ/RXRα heterodimer.
  • The study analyzed complexes of PPARγ/RXRα with DNA from a regulated gene and the TIF2 receptor interacting domain (RID).
  • Solution structures were determined to reveal the overall architecture and binding interfaces.

Main Results:

  • The solution structures demonstrated an asymmetrical organization of the PPARγ/RXRα heterodimer.
  • DNA binding was identified as a critical factor in positioning the heterodimer, inducing this asymmetry.
  • Asymmetrical binding of the TIF2 coactivator to the PPARγ/RXRα heterodimer was observed.

Conclusions:

  • DNA plays a crucial role in dictating the structural conformation of the PPARγ/RXRα heterodimer.
  • The observed asymmetry influences the interaction dynamics with coactivators such as TIF2.
  • These findings provide insights into the molecular mechanisms underlying PPARγ-mediated gene regulation.

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