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Originally published In Press as doi:10.1074/jbc.M100903200 on March 6, 2001

J. Biol. Chem., Vol. 276, Issue 20, 17044-17051, May 18, 2001
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Binding of Steroidogenic Acute Regulatory Protein to Synthetic Membranes Suggests an Active Molten Globule*

Kathrine ChristensenDagger , Himangshu S. Bose§, Faith M. HarrisDagger , Walter L. Miller§||, and John D. BellDagger **

From the Dagger  Department of Zoology, Brigham Young University, Provo, Utah 84602 and the § Department of Pediatrics and  Metabolic Research Unit, University of California, San Francisco, California 94143-0978

Steroidogenic acute regulatory protein (StAR) mediates cholesterol transport from the outer to the inner mitochondrial membrane during steroid biosynthesis. The mechanism of StAR's action is not established. To address mechanistic issues, we assessed the binding of StAR to artificial membranes by fluorescence resonance energy transfer using endogenous StAR tryptophan residues as the donor and dansyl-phosphatidylethanolamine in the bilayer as the acceptor. Mixing StAR with dansyl-labeled vesicles composed of phosphatidylcholine increased the fluorescence intensity of dansyl emission excited at 280 nm by 10-40%. This interaction was dependent on pH, with a maximum at pH 3.0-3.5 and essentially no change above pH 5. Binding experiments at different temperatures and various combinations of phosphatidylcholine, phosphatidylglycerol, cardiolipin, and cholesterol showed that binding involves an electrostatic step and one or more other steps. Although binding prefers a thermodynamically ordered bilayer, the rate-limiting step occurs either when the bilayer is in a fluid state or when there is cholesterol-induced membrane heterogeneity. Experiments with fluorescence and light scattering indicate that StAR binding promotes ordering and aggregation of anionic membranes. The inactive StAR mutant R182L had lower affinity for the membrane, and the partially active mutant L275P had intermediate affinity. Far-UV CD spectroscopy of StAR in PC membranes show more beta -structure than in aqueous buffers, and the presence of cardiolipin or cholesterol in the membrane fosters a molten globule state. Our data suggest that StAR binds to membranes in a partially unfolded molten globule state that is relevant to the activity of the protein.

* This work was supported by National Institutes of Health (NIH) Grants R01 DK37922 and U54 HD 34449 (to W. L. M.), NIH Grant K01 DK02762 (to H. S. B.), and National Science Foundation Grant MCB 9904597 (to J. D. B.).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.

|| To whom correspondence may be addressed. E-mail: wlmlab@itsa.ucsf.edu.

** To whom correspondence may be addressed. E-mail: john_bell@byu.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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