Heterodimeric interaction between retinoid X receptor alpha and orphan nuclear receptor OR1 reveals dimerization-induced activation as a novel mechanism of nuclear receptor activation.
OR1 is a member of the steroid/thyroid hormone nuclear receptor superfamily which has been described to mediate transcriptional responses to retinoids and oxysterols. On a DR4 response element, an OR1 heterodimer with the nuclear receptor retinoid X receptor alpha (RXR alpha) has been described to convey transcriptional activation in both the absence and presence of the RXR ligand 9-cis retinoic acid, the mechanisms of which have remained unclear. Here, we dissect the effects of RXR alpha and OR1 ligand-binding domain interaction on transcriptional regulation and the role of the respective carboxy-terminal activation domains (AF-2s) in the absence and presence of the RXR ligand, employing chimeras of the nuclear receptors containing the heterologous GAL4 DNA-binding domain as well as natural receptors. The results show that the interaction of the RXR and OR1 ligand-binding domains unleashes a transcription activation potential that is mainly dependent on the AF-2 of OR1, indicating that interaction with RXR activates OR1. This defines dimerization-induced activation as a novel function of heterodimeric interaction and mechanism of receptor activation not previously described for nuclear receptors. Moreover, we present evidence that activation of OR1 occurs by a conformational change induced upon heterodimerization with RXR.
Wiebel
F F
FF
Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden. franziska.wiebel@csb.ki.se
Gustafsson
J A
JA
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology; D019281:Dimerization; D005786:Gene Expression Regulation; D008969:Molecular Sequence Data; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D016415:Sequence Alignment; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors