Nuclear receptor coregulator (NRC): mapping of the dimerization domain, activation of p53 and STAT-2, and

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Published on: November 15, 2013

Muktar A Mahajan1, Audrey Murray, David Levy

  • 1Department of Pharmacology, New York University School of Medicine, New York, New York 10016, USA. muktar.mahajan@med.nyu.edu

Molecular Endocrinology (Baltimore, Md.)
|May 31, 2007
PubMed

Insights

Nuclear receptor coregulator (NRC) is a key protein in gene transcription. This study reveals a specific region crucial for NRC dimerization, nuclear receptor binding, and transcriptional activation.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Protein Structure and Function

Background:

  • Nuclear receptor coregulator (NRC) is a 250-kDa protein essential for transcriptional activation.
  • NRC possesses distinct domains: two activation domains (AD1, AD2), two nuclear hormone receptor-interacting motifs (LxxLL-1, LxxLL-2), and a C-terminal regulatory region.
  • LxxLL-1 binds diverse nuclear hormone receptors with high affinity, while LxxLL-2 interacts with limited receptors.

Purpose of the Study:

  • To investigate the dimerization of NRC.
  • To identify the specific region responsible for NRC dimerization and nuclear receptor interaction.
  • To elucidate the role of NRC domains in transcriptional activation.

Main Methods:

  • Dimerization assays to confirm NRC's dimeric nature.
  • Site-directed mutagenesis to analyze the function of LxxLL-1 and surrounding regions.
  • Functional assays to assess transcriptional activation mediated by NRC domains.

Main Results:

  • Evidence presented for NRC acting as a dimer, with a 146-amino acid region including LxxLL-1 identified as a dimerization region.
  • Mutation of the core LxxLL-1 motif did not affect dimerization, suggesting it's not directly involved.
  • Activation domain 2 (AD2) plays a critical role in ligand-dependent activation, despite AD1's higher intrinsic activity.
  • A ~300-amino acid region encompassing LxxLL-1 is vital for NRC dimerization, nuclear receptor binding, and transcriptional activation.
  • NRC also coactivates signal transducer and activator of transcription 2 (STAT-2) and p53.

Conclusions:

  • A specific region of NRC is critical for its dimerization, nuclear receptor binding, and transcriptional coactivation.
  • NRC's modular structure allows for diverse interactions, including coactivation of STAT-2 and p53 through novel mechanisms involving the mediator complex.

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