Identification of COUP-TFII orphan nuclear receptor as a retinoic acid-activated receptor.
The chicken ovalbumin upstream promoter-transcription factors (COUP-TFI and II) make up the most conserved subfamily of nuclear receptors that play key roles in angiogenesis, neuronal development, organogenesis, cell fate determination, and metabolic homeostasis. Although the biological functions of COUP-TFs have been studied extensively, little is known of their structural features or aspects of ligand regulation. Here we report the ligand-free 1.48 A crystal structure of the human COUP-TFII ligand-binding domain. The structure reveals an autorepressed conformation of the receptor, where helix alpha10 is bent into the ligand-binding pocket and the activation function-2 helix is folded into the cofactor binding site, thus preventing the recruitment of coactivators. In contrast, in multiple cell lines, COUP-TFII exhibits constitutive transcriptional activity, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, and ligand binding, substantially reduce the COUP-TFII transcriptional activity. Importantly, retinoid acids are able to promote COUP-TFII to recruit coactivators and activate a COUP-TF reporter construct. Although the concentration needed is higher than the physiological levels of retinoic acids, these findings demonstrate that COUP-TFII is a ligand-regulated nuclear receptor, in which ligands activate the receptor by releasing it from the autorepressed conformation.
Kruse
Schoen W
SW
Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan, USA.
Suino-Powell
Kelly
K
Zhou
X Edward
XE
Kretschman
Jennifer E
JE
Reynolds
Ross
R
Vonrhein
Clemens
C
Xu
Yong
Y
Wang
Liliang
L
Tsai
Sophia Y
SY
Tsai
Ming-Jer
MJ
Xu
H Eric
HE
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D051837:COUP Transcription Factor II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002645:Chickens; D018360:Crystallography, X-Ray; D019281:Dimerization; D005260:Female; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D014212:Tretinoin / Q000378:metabolism
D051837:COUP Transcription Factor II; D008024:Ligands; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; C095569:NR2F2 protein, human
Nature. 2002 Feb 14;415(6873):813-7
11845213
Mol Cell Biol. 1996 May;16(5):2332-40
8628300
Mol Cell. 2003 Jun;11(6):1575-85
12820970
Acta Crystallogr D Biol Crystallogr. 2003 Nov;59(Pt 11):2023-30
14573958
Genes Dev. 1998 Nov 1;12(21):3343-56
9808622
Science. 1999 Apr 30;284(5415):757-60
10221899
Genes Dev. 2001 Aug 15;15(16):2054-9
11511537
Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
15299374
Mol Cell. 2000 Mar;5(3):545-55
10882139
Keio J Med. 2003 Sep;52(3):174-81
14529150
Cell. 1995 Dec 15;83(6):851-7
8521509
Cell. 1997 Aug 8;90(3):569-80
9267036
Structure. 2002 Sep;10(9):1225-34
12220494
Cell. 2004 Feb 6;116(3):417-29
15016376
Mol Cell. 2004 Dec 22;16(6):893-905
15610733
Biochim Biophys Acta. 2000 Mar 27;1470(2):M63-8
10722928
Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21
9757107
Mol Endocrinol. 2005 Sep;19(9):2299-308
15890675
Nature. 1998 Sep 10;395(6698):137-43
9744270
Nature. 1995 Dec 14;378(6558):690-7
7501015
Methods Enzymol. 1997;276:307-26
27754618
Mol Cell. 2000 Feb;5(2):289-98
10882070
Genes Dev. 1997 Aug 1;11(15):1925-37
9271116
Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17868-73
17098861
Genes Dev. 2005 Mar 1;19(5):614-25
15741322
Nature. 1995 Dec 14;378(6558):681-9
7501014
Mol Cell Biol. 1997 Sep;17(9):4914-32
9271371
Genes Dev. 1999 Apr 15;13(8):1037-49
10215630
Nature. 1997 Oct 16;389(6652):753-8
9338790
Mol Cell Biol. 1999 Apr;19(4):2734-45
10082539
Nature. 2005 May 5;435(7038):98-104
15875024
J Biol Chem. 2000 Feb 4;275(5):3446-54
10652338
Nature. 1995 Jun 1;375(6530):377-82
7760929
Cell. 1995 Dec 15;83(6):841-50
8521508
Mol Cell. 2004 Feb 13;13(3):317-27
14967140
Mol Endocrinol. 2004 Apr;18(4):807-19
15044597
J Lipid Res. 2000 Jan;41(1):1-11
10627496
PLoS Genet. 2007 Jun;3(6):e102
17590085
Science. 1998 Jun 12;280(5370):1747-9
9624051
Cell. 1998 Dec 23;95(7):927-37
9875847
EMBO J. 2003 Sep 15;22(18):4625-33
12970175
J Biol Chem. 1997 Oct 31;272(44):27629-34
9346901
Cell. 2002 Jul 12;110(1):93-105
12151000
Pharmacol Rev. 2006 Dec;58(4):685-704
17132848
Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15358-63
14673100
Mol Cell. 2004 Dec 22;16(6):907-17
15610734
Mol Cell. 2005 Feb 18;17(4):491-502
15721253
Nature. 1989 Jul 13;340(6229):163-6
2739739
Mol Cell Biol. 1992 Sep;12(9):4153-63
1324415
Cell. 2005 Feb 11;120(3):343-55
15707893
Proc Natl Acad Sci U S A. 2005 Nov 8;102(45):16351-6
16251273
Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6293-8
17404209
Mol Cell Biol. 1986 Dec;6(12):4259-67
3796602
Endocr Rev. 1997 Apr;18(2):229-40
9101138
Structure. 2003 Jul;11(7):741-6
12842037
J Biol Chem. 2003 Jul 18;278(29):27138-43
12736258
Science. 1997 Aug 15;277(5328):965-8
9252329
Development. 2005 May;132(9):2179-89
15829524
EMBO J. 1999 Sep 1;18(17):4608-18
10469641
Acta Crystallogr D Biol Crystallogr. 2000 Oct;56(Pt 10):1316-23
10998628
Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9505-10
15976031
Mol Cell. 2003 Apr;11(4):1093-100
12718893
Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8479-84
9238002
Genes Dev. 2000 Sep 1;14(17):2229-41
10970886
Acta Crystallogr D Biol Crystallogr. 1994 Mar 1;50(Pt 2):178-85
15299456
J Mol Biol. 2006 Jul 14;360(3):586-98
16781732
Neuron. 1999 Dec;24(4):847-59
10624948
Mol Cell. 2005 Aug 5;19(3):367-80
16061183