| Structural highlights
Function
[STF1_MOUSE] Transcriptional activator. Seems to be essential for sexual differentiation and formation of the primary steroidogenic tissues. Binds to the Ad4 site found in the promoter region of steroidogenic P450 genes such as CYP11A, CYP11B and CYP21B. Also regulates the AMH/Muellerian inhibiting substance gene as well as the AHCH and STAR genes. 5'-YCAAGGYC-3' and 5'-RRAGGTCA-3' are the consensus sequences for the recognition by NR5A1. The SFPQ-NONO-NR5A1 complex binds to the CYP17 promoter and regulates basal and cAMP-dependent transcriptional avtivity (By similarity). Transcription repressor of the Moloney leukemia virus long terminal repeat in undifferentiated murine embryonal carcinoma cells. Binds phosphatidylcholine and phospholipids with a phosphatidylinositol (PI) headgroup, in particular phosphatidyl(3,4)bisphosphate, phosphatidyl(3,5)bisphosphate and phosphatidyl(3,4,5)triphosphate. Activated by the phosphorylation of NR5A1 by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation.[1] [2] [PRGC1_MOUSE] Transcriptional coactivator for steroid receptors and nuclear receptors. Greatly increases the transcriptional activity of PPARG and thyroid hormone receptor on the uncoupling protein promoter. Can regulate key mitochondrial genes that contribute to the program of adaptive thermogenesis. Plays an essential role in metabolic reprogramming in response to dietary availability through coordination of the expression of a wide array of genes involved in glucose and fatty acid metabolism.[3] [4]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Despite the fact that many nuclear receptors are ligand dependent, the existence of obligate regulatory ligands is debated for some receptors, including steroidogenic factor 1 (SF-1). Although fortuitously bound bacterial phospholipids were discovered in the structures of the SF-1 ligand-binding domain (LBD), these lipids might serve merely as structural ligands. Thus, we examined whether exogenously added phospholipids would exchange for these bacterial lipids and bind to SF-1. Here, we report the first crystal structure of the SF-1 LBD bound by the exchanged phosphatidylcholine. Although the bound phosphatidylcholine phospholipid mimics the conformation of bound bacterial phosphoplipids, two surface loops, L2-3 and L11-12, surrounding the entrance to the pocket vary significantly between different SF-1 LBD structures. Based on this observation, we hypothesized that a bound ligand might control the conformations of loops L2-3 and L11-12, and that conserved residues in these dynamic loops could influence ligand binding and the receptor function. Consistent with this hypothesis, impaired phospholipid exchange and diminished transcriptional activity were observed for loop L11-12 SF-1 mutants and for the loop L2-3 human mutant R255L. The endocrine disease associated with this L2-3 mutation coupled with our cellular and biochemical data suggest that critical residues at the mouth of the ligand-binding pocket have evolved for efficient binding of phospholipid ligands and for achieving optimal SF-1 activity.
Structure of SF-1 bound by different phospholipids: evidence for regulatory ligands.,Sablin EP, Blind RD, Krylova IN, Ingraham JG, Cai F, Williams JD, Fletterick RJ, Ingraham HA Mol Endocrinol. 2009 Jan;23(1):25-34. Epub 2008 Nov 6. PMID:18988706[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lan HC, Li HJ, Lin G, Lai PY, Chung BC. Cyclic AMP stimulates SF-1-dependent CYP11A1 expression through homeodomain-interacting protein kinase 3-mediated Jun N-terminal kinase and c-Jun phosphorylation. Mol Cell Biol. 2007 Mar;27(6):2027-36. Epub 2007 Jan 8. PMID:17210646 doi:10.1128/MCB.02253-06
- ↑ Sablin EP, Blind RD, Krylova IN, Ingraham JG, Cai F, Williams JD, Fletterick RJ, Ingraham HA. Structure of SF-1 bound by different phospholipids: evidence for regulatory ligands. Mol Endocrinol. 2009 Jan;23(1):25-34. Epub 2008 Nov 6. PMID:18988706 doi:10.1210/me.2007-0508
- ↑ Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998 Mar 20;92(6):829-39. PMID:9529258
- ↑ Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005 Mar 3;434(7029):113-8. PMID:15744310 doi:http://dx.doi.org/10.1038/nature03354
- ↑ Sablin EP, Blind RD, Krylova IN, Ingraham JG, Cai F, Williams JD, Fletterick RJ, Ingraham HA. Structure of SF-1 bound by different phospholipids: evidence for regulatory ligands. Mol Endocrinol. 2009 Jan;23(1):25-34. Epub 2008 Nov 6. PMID:18988706 doi:10.1210/me.2007-0508
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