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

doi:10.1016/s0092-8674(03)00420-3

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

Cell. 2003 Jun 13;113(6):731-42. doi: 10.1016/s0092-8674(03)00420-3.

Authors

Keith D Baker¹, 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

Affiliation

¹ Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.

PMID: 12809604
DOI: 10.1016/s0092-8674(03)00420-3

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Binding Sites / physiology
Cell Line
Cell Nucleus / metabolism*
DNA-Binding Proteins / metabolism*
Drosophila Proteins*
Drosophila melanogaster / cytology
Drosophila melanogaster / growth & development*
Drosophila melanogaster / metabolism
Ecdysteroids / metabolism*
Larva / cytology
Larva / growth & development*
Larva / metabolism
Metamorphosis, Biological / physiology*
Models, Molecular
Nuclear Receptor Subfamily 4, Group A, Member 1
Protein Structure, Secondary / physiology
Protein Structure, Tertiary / physiology
Receptors, Cytoplasmic and Nuclear / metabolism*
Receptors, Steroid / metabolism
Signal Transduction / physiology
Transcription Factors / metabolism

Substances

DNA-Binding Proteins
Drosophila Proteins
Ecdysteroids
Hr38 protein, Drosophila
NR4A1 protein, human
Nuclear Receptor Subfamily 4, Group A, Member 1
Receptors, Cytoplasmic and Nuclear
Receptors, Steroid
Transcription Factors
USP protein, Drosophila
ecdysteroid receptor

Associated data

PDB/1PDU