M. Ito et al., A naturally occurring steroidogenic factor-1 mutation exhibits differential binding and activation of target genes, J BIOL CHEM, 275(41), 2000, pp. 31708-31714
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 mu
tation 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 res
ponse elements. However, mutant SF-l bound to a subset of response elements
containing a CCA AGGTCA motif. Mutagenesis studies of response elements re
vealed that the first nucleotide position in the 5'-flanking sequence tripl
et 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, elimin
ated binding by mutant SF-1 to all response elements tested. These data sup
port the idea that the A-box stabilizes monomeric binding by nuclear recept
ors. This action may be particularly important when P-box binding affinity
is compromised either by mutations in SF-l or by sequence alterations in it
s binding site.