The Drosophila orphan nuclear receptor DHR38 mediates an atypical ecdysteroid signaling pathway.
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.
Baker
Keith D
KD
Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Shewchuk
Lisa M
LM
Kozlova
Tatiana
T
Makishima
Makoto
M
Hassell
Annie
A
Wisely
Bruce
B
Caravella
Justin A
JA
Lambert
Millard H
MH
Reinking
Jeffrey L
JL
Krause
Henry
H
Thummel
Carl S
CS
Willson
Timothy M
TM
Mangelsdorf
David J
DJ
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D026461:Ecdysteroids / Q000378:metabolism*; D007814:Larva / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D008675:Metamorphosis, Biological / Q000502:physiology*; D008958:Models, Molecular; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D017433:Protein Structure, Secondary / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D026461:Ecdysteroids; C095176:Hr38 protein, Drosophila; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; C066030:USP protein, Drosophila; C034808:ecdysteroid receptor