Structural basis for corepressor assembly by the orphan nuclear receptor TLX

Area of Science:

• Molecular Biology
• Neuroscience
• Structural Biology

Background:

• The orphan nuclear receptor TLX (tailless homolog) is crucial for neural stem cell self-renewal in the adult brain.
• TLX primarily functions as a transcription repressor, recruiting Atrophin corepressors via a conserved Atro box motif.

Purpose of the Study:

• To elucidate the structural basis of TLX-mediated transcriptional repression.
• To identify the key interactions between TLX and Atrophin corepressors.

Main Methods:

• Crystal structure determination of human and insect TLX ligand-binding domain (LBD) in complex with Atro box peptides.
• Site-directed mutagenesis to assess the impact of altered TLX-Atrophin interactions on repressor activity.

Main Results:

• Crystal structures reveal TLX in an autorepressed conformation with helix H12 occupying the coactivator-binding groove.
• A novel binding pocket is formed by helix H3 and H12, accommodating a helix from the Atro box peptide (ALXXLXXY motif).
• Mutations disrupting the TLX-Atrophin interaction abolish TLX's repressive activity.

Conclusions:

• The study defines a conserved autorepressed conformation in TLX and other repressor nuclear receptors.
• A specific sequence motif within the Atro box is essential for TLX-mediated repression.
• The findings provide structural insights into the mechanism of transcriptional repression by orphan nuclear receptors.