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Papers In Press, published online ahead of print March 6, 2001
Department of Zoology, Brigham Young University, Provo, UT 84602
Corresponding Author: john_bell{at}byu.edu
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 (PC) 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
J. Biol. Chem, 10.1074/jbc.M100903200
Submitted on January 31, 2001
Revised on March 5, 2001
Accepted on March 5, 2001
Binding of StAR to synthetic membranes suggests an active molten globule
-structure than in aqueous buffers, and the presence of cardiolipin or cholesterol in the membrane foster a molten globule state. Our data suggest that StAR binds to membranes in a partially unfolded molten globule state that is relevant to StAR's activity of the protein.
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