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Related Experiment Videos

Active, interactive, and inactive steroid receptor mutants

R B Lanz1, M Hug, M Gola

  • 1Institüt für Molekularbiologie II der Universität Zürich, Switzerland.

Steroids
|February 1, 1994
PubMed
Summary

Glucocorticoid receptor (GR) domain interactions were studied. Mutations reveal key roles for ligand binding and poly-Gln repeats in transactivation, offering tools for functional analysis.

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Area of Science:

  • Molecular Biology
  • Endocrinology
  • Genetics

Background:

  • The glucocorticoid receptor (GR) is a crucial nuclear receptor involved in various physiological processes.
  • Understanding the intricate domain interactions within GR is essential for deciphering its regulatory mechanisms.

Purpose of the Study:

  • To investigate the cross-interactions between different domains of the glucocorticoid receptor (GR).
  • To identify specific mutations that modulate GR activity, DNA binding, and ligand response.
  • To explore the functional impact of altered CAG repeat frames on GR transactivation.

Main Methods:

  • Transient co-transfection assays were employed to study GR domain interactions.
  • Site-directed mutagenesis was used to alter specific amino acid residues and CAG repeat frames.

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  • Analysis of transactivation, DNA binding, and ligand binding was performed.

    • Main Results:

    • A mutation at Ile484 (rat GR) to cysteine separated transactivation from DNA binding.
    • The ligand binding domain was found to be critical for cooperative transactivation.
    • Carboxy-terminal mutations altered GR responses to agonists and antagonists.
    • Altered reading frames of the CAG repeat, producing poly-Ala, resulted in a trans-dominant negative phenotype affecting GR transactivation without impacting DNA or ligand binding.

    Conclusions:

    • Extensive cross-talk exists between GR domains, influencing its function.
    • Specific mutations can decouple DNA binding from transactivation and modulate ligand sensitivity.
    • The trans-dominant negative effect of poly-Ala from altered CAG repeats provides a valuable tool for GR functional studies in vivo.