期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 275, 期 41, 页码 31708-31714出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M002892200
关键词
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资金
- NICHD NIH HHS [P01-HD-21921, U54-HD-29164] Funding Source: Medline
Steroidogenic factor-1 (SF-l) is an orphan nuclear receptor that binds DNA as a monomer and regulates the transcription of multiple target genes. A mutation in the proximal (P)-box of the first zinc finger of SF-l (G35E) has been reported to cause complete XY sex reversal and adrenal insufficiency. Because this P-box region dictates DNA binding specificity, we investigated the effect of this mutation on DNA binding and regulation of target genes. Binding of the P-box mutant was markedly impaired for most native SF-1 response elements. However, mutant SF-l bound to a subset of response elements containing a CCA AGGTCA motif. Mutagenesis studies of response elements revealed that the first nucleotide position in the 5'-flanking sequence triplet and the central part of the half-site dictate DNA binding specificity by the mutant SF-1. Further, introduction of a mutation into the SF-l A-box, which has been proposed to bind to the 5'-flanking sequence triplet, eliminated binding by mutant SF-1 to all response elements tested. These data support the idea that the A-box stabilizes monomeric binding by nuclear receptors. This action may be particularly important when P-box binding affinity is compromised either by mutations in SF-l or by sequence alterations in its binding site.
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