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

被引:195
作者
Baker, KD
Shewchuk, LM
Kozlova, T
Makishima, M
Hassell, A
Wisely, B
Caravella, JA
Lambert, MH
Reinking, JL
Krause, H
Thummel, CS
Willson, TM
Mangelsdorf, DJ
机构
[1] Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dallas, TX 75390 USA
[2] Univ Texas, SW Med Ctr, Dept Pharmacol, Dallas, TX 75390 USA
[3] GlaxoSmithKline, Discovery Res, Res Triangle Pk, NC 27709 USA
[4] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA
[5] Univ Utah, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA
[6] Univ Toronto, Ontario Canc Inst, Toronto, ON M5G 2C4, Canada
[7] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2C4, Canada
[8] Univ Toronto, Charles H Best Inst, Banting & Best Dept Med Res, Toronto, ON M5G 1L6, Canada
关键词
D O I
10.1016/S0092-8674(03)00420-3
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:731 / 742
页数:12
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