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Molecular and Cellular Biology, October 2002, p. 7193-7203, Vol. 22, No. 20
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.20.7193-7203.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Phosphorylation and Intramolecular Stabilization of the Ligand Binding Domain in the Nuclear Receptor Steroidogenic Factor 1

Marion Desclozeaux,1 Irina N. Krylova,1 Florence Horn,2 Robert J. Fletterick,3 and Holly A. Ingraham1*

Departments of Physiology,1 Cellular and Molecular Pharmacology,2 Biochemistry and Biophysics University of California San Francisco, San Francisco, California 94143-04443

Received 20 February 2002/ Returned for modification 8 April 2002/ Accepted 8 July 2002

Steroidogenic factor 1 (SF-1) is an orphan nuclear receptor with no known ligand. We showed previously that phosphorylation at serine 203 located N'-terminal to the ligand binding domain (LBD) enhanced cofactor recruitment, analogous to the ligand-mediated recruitment in ligand-dependent receptors. In this study, results of biochemical analyses and an LBD helix assembly assay suggest that the SF-1 LBD adopts an active conformation, with helices 1 and 12 packed against the predicted alpha-helical bundle, in the apparent absence of ligand. Fine mapping of the previously defined proximal activation function in SF-1 showed that the activation function mapped fully to helix 1 of the LBD. Limited proteolyses demonstrate that phosphorylation of S203 in the hinge region mimics the stabilizing effects of ligand on the LBD. Moreover, similar effects were observed in an SF-1/thyroid hormone LBD chimera receptor, illustrating that the S203 phosphorylation effects are transferable to a heterologous ligand-dependent receptor. Our collective data suggest that the hinge together with helix 1 is an individualized specific motif, which is tightly associated with its cognate LBD. For SF-1, we find that this intramolecular association and hence receptor activity are further enhanced by mitogen-activated protein kinase phosphorylation, thus mimicking many of the ligand-induced changes observed for ligand-dependent receptors.

* Corresponding author. Mailing address: Department of Physiology, S1479D, UCSF, 513 Parnassus Ave., San Francisco, CA 94143-0444. Phone: (415) 476-2731. Fax: (415) 476-4929. E-mail: hollyi{at}itsa.ucsf.edu.

Molecular and Cellular Biology, October 2002, p. 7193-7203, Vol. 22, No. 20
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.20.7193-7203.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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