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Originally published In Press as doi:10.1074/jbc.M002892200 on July 25, 2000

J. Biol. Chem., Vol. 275, Issue 41, 31708-31714, October 13, 2000
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A Naturally Occurring Steroidogenic Factor-1 Mutation Exhibits Differential Binding and Activation of Target Genes*

Masafumi ItoDagger , John C. AchermannDagger , and J. Larry Jameson§

From the Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, Illinois 60611

Steroidogenic factor-1 (SF-1) 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-1 (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-1 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-1 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-1 or by sequence alterations in its binding site.

* This work was performed as part of the National Institutes of Health Grants U54-HD-29164 and PO1·HD-21921.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger The first two authors contributed equally to this work.

§ To whom correspondence should be addressed: Div. of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Tarry Bldg. 15-709, 303 E. Chicago Ave., Chicago, IL 60611. Tel.: 312-503-0469; Fax: 312-503-0474; E-mail: ljameson@northwestern.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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