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J. Biol. Chem., Vol. 276, Issue 40, 36970-36982, October 5, 2001
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From the The steroidogenic acute regulatory protein (StAR)
mediates the rate-limiting step of steroidogenesis, delivery of
cholesterol to the inner mitochondrial membrane. However, the mechanism
whereby cholesterol translocation is accomplished has not been
resolved. Recombinant StAR proteins lacking the first N-terminal 62 amino acids comprising the mitochondrial-targeting sequence were used to determine if StAR binds cholesterol and alters mitochondrial membrane cholesterol domains to enhance sterol transfer. First, a
fluorescent NBD-cholesterol binding assay revealed 2 sterol binding
sites (Kd values near 32 nM), whereas
the inactive A218V N-62 StAR mutant had only a single binding site with
8-fold lower affinity. Second, NBD-cholesterol spectral shifts and
fluorescence resonance energy transfer from StAR Trp residues to
NBD-cholesterol showed (i) close molecular interaction between these
molecules (R2/3 = 33 Å) and (ii) sensitized
NBD-cholesterol emission from only one of the two sterol binding sites.
Third, circular dichroism showed that cholesterol binding induced a
change in StAR secondary structure. Fourth, a fluorescent sterol
transfer assay that did not require separation of donor and acceptor
mitochondrial membranes demonstrated that StAR enhanced mitochondrial
sterol transfer as much as 100-fold and induced/increased the formation of rapidly transferable cholesterol domains in isolated mitochondrial membranes. StAR was 67-fold more effective in transferring cholesterol from mitochondria of steroidogenic MA-10 cells than from human fibroblast mitochondria. In contrast, sterol carrier protein-2 (SCP-2)
was only 2.2-fold more effective in mediating sterol transfer from
steroidogenic cell mitochondria. Taken together these data showed that
StAR is a cholesterol-binding protein, preferentially enhances sterol
transfer from steroidogenic cell mitochondria, and interacts with
mitochondrial membranes to alter their sterol domain structure and dynamics.
Steroidogenic Acute Regulatory Protein Binds Cholesterol
and Modulates Mitochondrial Membrane Sterol Domain Dynamics*
,,¶
Department of Physiology and Pharmacology,
Texas A&M University, College Station, Texas 77843-4466 and the
§ Center for Research on Reproduction and Women's Health,
University of Pennsylvania Medical Center,
Philadelphia, Pennsylvania 19104
*
This work was supported in part by the United States Public
Health Service National Institutes of Health Grants GM31651 (to F. S.)
and HD06274 (to J. F. S.) and National Cooperative Program in
Infertility Research (NCPIR) Grant HD34449 (to J. F. S.).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.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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