The Drosophila orphan nuclear receptor DHR38 mediates an atypical ecdysteroid signaling pathway

Keith D. Baker, Lisa M. Shewchuk, Tatiana Kozlova, Makoto Makishima, Annie Hassell, Bruce Wisely, Justin A. Caravella, Millard H. Lambert, Jeffrey L. Reinking, Henry Krause, Carl S. Thummel, Timothy M. Willson, David J. Mangelsdorf

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181 Scopus citations

Abstract

Ecdysteroid pulses trigger the major developmental transitions during the Drosophila life cycle. These hormonal responses are thought to be mediated by the ecdysteroid receptor (EcR) and its heterodimeric partner Ultraspiracle (USP). We provide evidence for a second ecdysteroid signaling pathway mediated by DHR38, the Drosophila ortholog of the mammalian NGFI-B subfamily of orphan nuclear receptors. DHR38 also heterodimerizes with USP, and this complex responds to a distinct class of ecdysteroids in a manner that is independent of EcR. This response is unusual in that it does not involve direct binding of ecdysteroids to either DHR38 or USP. X-ray crystallographic analysis of DHR38 reveals the absence of both a classic ligand binding pocket and coactivator binding site, features that seem to be common to all NGFI-B subfamily members. Taken together, these data reveal the existence of a separate structural class of nuclear receptors that is conserved from fly to humans.

Original languageEnglish (US)
Pages (from-to)731-742
Number of pages12
JournalCell
Volume113
Issue number6
DOIs
StatePublished - Jun 13 2003

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Baker, K. D., Shewchuk, L. M., Kozlova, T., Makishima, M., Hassell, A., Wisely, B., Caravella, J. A., Lambert, M. H., Reinking, J. L., Krause, H., Thummel, C. S., Willson, T. M., & Mangelsdorf, D. J. (2003). The Drosophila orphan nuclear receptor DHR38 mediates an atypical ecdysteroid signaling pathway. Cell, 113(6), 731-742. https://doi.org/10.1016/S0092-8674(03)00420-3