Another Orphan Receptor Finds a Home♦

The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor
    Open AccessPublished:January 28, 2011DOI:
        ♦ See referenced article, J. Biol. Chem. 2011, 286, 2877–2885
        Testicular receptors 2 and 4 (TR2/4) are a class of orphan nuclear receptors that play important roles in spermatogenesis, lipid regulation, and other processes. Like other orphan receptors, though, the lack of structural or ligand data for TR2/4 has made their exact function unclear. However, in this Paper of the Week, X. Edward Zhou and colleagues provide some valuable structural insights into this receptor family. They solved a 3.0 Å crystal structure of the TR4 ligand binding domain, revealing an autorepressed conformation in which both the ligand and cofactor binding sites were occupied by other segments of TR4, thus preventing ligand-independent activation; this structure is reminiscent of the ligand-free structure of COUP-TFII and retinoid X receptor α. Consistent with this observation, Zhou and colleagues found that retinol and retinoic acid promote coactivator recruitment and transcriptional activation in TR4. This study demonstrates that TR4 is a ligand-regulated receptor and provides support for an expanded signaling network that involves vitamin A beyond the classic retinoic acid receptor pathways.
        Figure thumbnail gr1
        Close-up view of the ligand-binding pocket of ligand-free TR4, shown to be occupied by large hydrophobic side chains.