Identification of COUP-TFII orphan nuclear receptor as a retinoic acid-activated receptor
| Autor: | Clemens Vonrhein, Schoen W. Kruse, Jennifer E Kretschman, Ross Reynolds, Yong Xu, Sophia Y. Tsai, Liliang Wang, Ming-Jer Tsai, H. Eric Xu, Kelly Suino-Powell, X. Edward Zhou |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Models
Molecular Receptors Retinoic Acid QH301-705.5 Molecular Sequence Data Biophysics Tretinoin Retinoid X receptor Biology Crystallography X-Ray Ligands Biochemistry General Biochemistry Genetics and Molecular Biology Cell Line COUP Transcription Factor II 03 medical and health sciences 0302 clinical medicine Animals Humans Amino Acid Sequence Biology (General) Protein Structure Quaternary Molecular Biology Nuclear receptor co-repressor 1 030304 developmental biology 0303 health sciences Binding Sites General Immunology and Microbiology Retinoid X receptor alpha General Neuroscience Retinoic acid receptor gamma Retinoid X receptor gamma 3. Good health Protein Structure Tertiary Retinoic acid receptor Retinoic acid receptor alpha 030220 oncology & carcinogenesis Estrogen-related receptor gamma Female General Agricultural and Biological Sciences Chickens Dimerization Sequence Alignment Research Article |
| Zdroj: | PLoS Biology, Vol 6, Iss 9, p e227 (2008) PLoS Biology |
| ISSN: | 1545-7885 1544-9173 |
| Popis: | The chicken ovalbumin upstream promoter-transcription factors (COUP-TFI and II) make up the most conserved subfamily of nuclear receptors that play key roles in angiogenesis, neuronal development, organogenesis, cell fate determination, and metabolic homeostasis. Although the biological functions of COUP-TFs have been studied extensively, little is known of their structural features or aspects of ligand regulation. Here we report the ligand-free 1.48 Å crystal structure of the human COUP-TFII ligand-binding domain. The structure reveals an autorepressed conformation of the receptor, where helix α10 is bent into the ligand-binding pocket and the activation function-2 helix is folded into the cofactor binding site, thus preventing the recruitment of coactivators. In contrast, in multiple cell lines, COUP-TFII exhibits constitutive transcriptional activity, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, and ligand binding, substantially reduce the COUP-TFII transcriptional activity. Importantly, retinoid acids are able to promote COUP-TFII to recruit coactivators and activate a COUP-TF reporter construct. Although the concentration needed is higher than the physiological levels of retinoic acids, these findings demonstrate that COUP-TFII is a ligand-regulated nuclear receptor, in which ligands activate the receptor by releasing it from the autorepressed conformation. Author Summary Unlike other classes of receptors, nuclear receptors can bind directly to DNA and act as transcription factors, playing key roles in embryonic development and cellular metabolism. Most nuclear receptors are activated by signal-triggering molecules (ligands) and can regulate their activity by recruiting coactivator proteins. However, the ligands are unknown for a subset of “orphan” nuclear receptors, including the chicken ovalbumin promoter-transcription factors (COUP-TFI and II, and EAR2). COUP-TFs are the most conserved nuclear receptors, with roles in angiogenesis, neuronal development, organogenesis, and metabolic homeostasis. Here we demonstrate that COUP-TFII is a ligand-regulated nuclear receptor that can be activated by unphysiological micromolar concentrations of retinoic acids. We determined the structure of the ligand-free ligand-binding domain of the human COUP-TFII, revealing the autorepressed conformation of the receptor, where helix α10 is bent into the ligand-binding pocket and the activation function-2 helix is folded into the cofactor binding site, thus preventing the recruitment of coactivators. These results suggest a mechanism where ligands activate COUP-TFII by releasing the receptor from the autorepressed conformation. The identification of COUP-TFII as a low-affinity retinoic acid receptor suggests ways of searching for the endogenous ligands that may ultimately link retinoic acid and COUP-TF signaling pathways. Structural and functional studies reveal that the orphan nuclear receptor COUP-TFII is a low-affinity receptor for retinoic acids. paving the way to finding the endogenous ligands that may ultimately link retinoic acid and COUP-TF signaling pathways. |
| Databáze: | OpenAIRE |
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