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J. Biol. Chem., Vol. 280, Issue 50, 41753-41760, December 16, 2005

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A pH-dependent Molten Globule Transition Is Required for Activity of the Steroidogenic Acute Regulatory Protein, StAR^*

Bo Y. Baker, Dustin C. Yaworsky1, and Walter L. Miller2

From the Department of Pediatrics and Metabolic Research Unit and Department of Pharmaceutical Chemistry Mass Spectrometry Facility, University of California, San Francisco, California 94143

The steroidogenic acute regulatory protein (StAR) simulates steroid biosynthesis by increasing the flow of cholesterol from the outer mitochondrial membrane (OMM) to the inner membrane. StAR acts exclusively on the OMM, and only StAR's carboxyl-terminal -helix (C-helix) interacts with membranes. Biophysical studies have shown that StAR becomes a molten globule at acidic pH, but a physiologic role for this structural transition has been controversial. Molecular modeling shows that the C-helix, which forms the floor of the sterol-binding pocket, is stabilized by hydrogen bonding to adjacent loops. Molecular dynamics simulations show that protonation of the C-helix and adjacent loops facilitates opening and closing the sterol-binding pocket. Two disulfide mutants, S100C/S261C (SS) and D106C/A268C (DA), designed to limit the mobility of the C-helix but not disrupt overall conformation, were prepared in bacteria, and their correct folding and positioning of the disulfide bonds was confirmed. The SS mutant lost half, and the DA mutant lost all cholesterol binding capacity and steroidogenic activity with isolated mitochondria in vitro, but full binding and activity was restored to each mutant by disrupting the disulfide bonds with dithiothreitol. These data strongly support the model that StAR activity requires a pH-dependent molten globule transition on the OMM.

Received for publication, September 19, 2005 , and in revised form, October 13, 2005.

^* This work was supported by National Institutes of Health Grant DK37922 (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.

¹ Present address: Agilent Technologies, Inc., Santa Clara, CA 95051-7210.

² To whom correspondence should be addressed: Dept. of Pediatrics, Bldg. MR-IV, Rm. 209, University of California, San Francisco, San Francisco, CA 94143-0978. Tel.: 415-476-2598; Fax: 415-476-6286, E-mail: wlmlab{at}itsa.ucsf.edu.

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