Co-repressor release but not ligand binding is a prerequisite for transcription activation by human retinoid acid receptor α ligand-binding domain

Hung Ying Kao, Chris C. Han, Anton A. Korma, Ronald M. Evans

研究成果: Article同行評審

12 引文 斯高帕斯(Scopus)

摘要

Nuclear hormone receptors coordinately regulate the activity of genetic networks through the recruitment of transcriptional co-regulators, including co-repressors and co-activators. Allosteric modulation of the ligand-binding domain by hormonal activators shifts the co-factor binding preference by defined structural changes in overlapping docking sites. We report here that mutations at conserved residues within the docking motif of the retinoic acid receptor α cause defects in dimerization, co-regulator association, and transcriptional regulation. Furthermore, although a minimal co-repressor receptor interaction domain is sufficient for receptor binding, flanking sequences appear to stabilize this interaction without interfering with ligand sensitivity. However, ligand sensitivity is changed by the K262A mutation, which requires much higher concentrations of all-trans-retinoic acid to promote co-repressor dissociation. Consequently, K262A functions as a dominant-negative mutant at low concentrations of all-trans-retinoic acid. As a result, transcriptional activation is mechanistically linked to co-repressor release.

原文English
頁(從 - 到)7366-7373
頁數8
期刊Journal of Biological Chemistry
278
發行號9
DOIs
出版狀態Published - 2003 二月 28

All Science Journal Classification (ASJC) codes

  • 生物化學
  • 分子生物學
  • 細胞生物學

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