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J. Biol. Chem., Vol. 283, Issue 14, 8837-8845, April 4, 2008

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Steroidogenic Activity of StAR Requires Contact with Mitochondrial VDAC1 and Phosphate Carrier Protein^*

Mahuya Bose, Randy M. Whittal, Walter L. Miller^¶, and Himangshu S. Bose¹

From the Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida 32610, the Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada, and the ^¶Department of Pediatrics, University of California, San Francisco, California 94143

The steroidogenic acute regulatory protein (StAR) is required for adrenal and gonadal steroidogenesis and for male sexual differentiation. StAR acts on the outer mitochondrial membrane (OMM) to facilitate movement of cholesterol from the OMM to the inner mitochondrial membrane to be converted to pregnenolone, the precursor of all steroid hormones. The mechanisms of the action of StAR remain unclear; the peripheral benzodiazepine receptor, an OMM protein, appears to be involved, but the identity of OMM proteins that interact with StAR remain unknown. Here we demonstrate that phosphorylated StAR interacts with voltage-dependent anion channel 1 (VDAC1) on the OMM, which then facilitates processing of the 37-kDa phospho-StAR to the 32-kDa intermediate. In the absence of VDAC1, phospho-StAR is degraded by cysteine proteases prior to mitochondrial import. Phosphorylation of StAR by protein kinase A requires phosphate carrier protein on the OMM, which appears to interact with StAR before it interacts with VDAC1. VDAC1 and phosphate carrier protein are the first OMM proteins shown to contact StAR.

Received for publication, November 9, 2007 , and in revised form, January 14, 2008.

^* This work was supported by grants from Pfizer, the March of Dimes, the American Heart Association, a start up package from the Howard Hughes Medical Institute (to H. B.), and National Institutes of Health Grant DK37922 and a Bridge Grant from the Endocrine Society (to W. L. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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¹ To whom correspondence should be addressed: Dept. of Biomedical Sciences, Mercer University School of Medicine, 4700 Waters Ave., Savannah, GA 31404. Fax: 912-350-8998; E-mail: bosehi1{at}memorialhealth.com.

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