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Modulation of RXR-DNA complex assembly by DNA context.

Judit Osz1, Alastair G McEwen1, Justine Wolf1

  • 1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM), U1258/Centre National de la Recherche Scientifique (CNRS), UMR7104/Université de Strasbourg, 67404, Illkirch, France.

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Retinoid X Receptors (RXRs) binding to DNA is modulated by variations in response elements. These sequence changes impact receptor function and protein interactions, affecting gene regulation.

Keywords:
DNAHomodimerNMRNuclear receptorRXRX-ray crystallography

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Area of Science:

  • Molecular Biology
  • Structural Biology
  • Genetics

Background:

  • Retinoid X Receptors (RXRs) are crucial nuclear receptors that regulate gene transcription through DNA binding.
  • RXRs function as homodimers, recognizing specific DNA sequences known as direct repeats of 1 nucleotide (DR1).
  • Variations within these DR1 sequences can influence RXR function, binding affinity, and conformational states.

Purpose of the Study:

  • To investigate the molecular mechanisms of RXR DNA interactions.
  • To understand how variations in DR1 sequences affect RXR DNA binding and function.

Main Methods:

  • Thermodynamics
  • X-ray crystallography
  • Nuclear Magnetic Resonance (NMR) spectroscopy, including chemical shift perturbation experiments.

Main Results:

  • Half-site sequences of DR1 significantly modulate the binding cooperativity between RXR DNA-binding domains (DBDs).
  • Sequence variations propagate conformational changes from the DNA-binding interface to the dimerization interface within the RXR DBD.
  • NMR data revealed specific changes in protein structure and dynamics in response to altered DNA sequences.

Conclusions:

  • DR1 sequence variations are critical determinants of RXR homodimer binding and function.
  • Understanding these sequence-specific interactions provides insight into the regulation of RXR-mediated gene transcription.
  • The study elucidates how subtle DNA sequence changes can lead to significant alterations in protein behavior and biological outcomes.