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Related Experiment Videos

Coactivators for the orphan nuclear receptor RORalpha.

G B Atkins1, X Hu, M G Guenther

  • 1Department of Medicine, The Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia 19104-6149, USA.

Molecular Endocrinology (Baltimore, Md.)
|September 9, 1999
PubMed
Summary

RORalpha, a nuclear orphan receptor crucial for cerebellar development, interacts with coactivators like GRIP-1 and PBP. GRIP-1 is identified as the first proven coactivator for RORalpha, independent of ligand binding.

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Area of Science:

  • Molecular Biology
  • Neuroscience
  • Endocrinology

Background:

  • RORalpha is a nuclear orphan receptor implicated in cerebellar development.
  • Mutations in RORalpha lead to severe cerebellar developmental defects.
  • RORalpha possesses a constitutive activation domain in its C-terminus.

Purpose of the Study:

  • To identify mammalian coactivators for the nuclear orphan receptor RORalpha.
  • To investigate the interaction mechanisms between RORalpha and its coactivators.
  • To determine if RORalpha coactivators function independently of ligand binding.

Main Methods:

  • Yeast two-hybrid screening using the RORalpha activation domain as bait.
  • In vitro interaction assays to confirm binding.

Related Experiment Videos

  • Mammalian cell co-transfection assays to assess coactivator function.
  • Analysis of protein complex formation in the absence of ligand.

    • Main Results:

    • Identified glucocorticoid receptor-interacting protein-1 (GRIP-1) and peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP) as RORalpha coactivators.
    • Confirmed interactions require the intact RORalpha activation domain, with distinct requirements for GRIP-1 and PBP.
    • Demonstrated that RORalpha interacts with coactivator complexes (including PBP and GRIP-1) in the absence of ligand.
    • GRIP-1 successfully functioned as a RORalpha coactivator in both yeast and mammalian cells.

    Conclusions:

    • GRIP-1 is the first validated coactivator for RORalpha.
    • RORalpha coactivators can interact with the receptor independently of ligand binding.
    • These findings provide insights into the molecular mechanisms underlying RORalpha's role in cerebellar development.