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PDBsum entry 1ilj
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Lipid binding protein
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PDB id
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1ilj
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References listed in PDB file
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Key reference
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Title
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Insights into steroidogenic acute regulatory protein (star)-Dependent cholesterol transfer in mitochondria: evidence from molecular modeling and structure-Based thermodynamics supporting the existence of partially unfolded states of star.
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Authors
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A.P.Mathieu,
A.Fleury,
L.Ducharme,
P.Lavigne,
J.G.Lehoux.
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Ref.
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J Mol Endocrinol, 2002,
29,
327-345.
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PubMed id
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Abstract
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The steroidogenic acute regulatory protein (StAR) is the major entrance for
cholesterol in mitochondria under acute stimulation. Under such circumstances,
dysfunctional StAR activity can ultimately lead to lipoid congenital adrenal
hyperplasia (LCAH). A complete understanding of the StAR's molecular structure
and mechanism is essential to comprehend LCAH. Thus far, there is no mechanistic
model that can explain experimental results at the molecular level. This is
partly due to the lack of the molecular structure of StAR. The closest
approximation to the StAR molecular structure is the human MLN64 which has a
similar activity to StAR, has a highly homologous primary structure and for
which an X-ray structure is known. In this context, we have modeled the
structure of StAR through standard homology modeling procedures based on the
MLN64 structure. Our StAR model shows the presence of a hydrophobic cavity of
783.9 A(2) in surface area, large enough to fit one molecule of cholesterol. In
addition, we have identified a unique charged pair, as in MLN64, lining the
surface of the cavity and which could play a key role in the binding of
cholesterol through the formation of an H-bond with its OH moiety. This suggests
that the cholesterol-binding site of StAR is located inside this cavity. Taking
into account that internal cavities are destabilizing to native protein
structures and that the lining of the cavity has to become accessible in order
to allow cholesterol binding, we have explored the possibility that StAR could
exist in equilibrium with partially unfolded states. Using a structure-based
thermodynamics approach, we show that partially folded states (with an unfolded
C-terminal alpha-helix, and an open cavity) can be significantly populated at
equilibrium and therefore allow cholesterol binding. These results are supported
by recent experiments that show a loss of StAR helical character upon binding of
an analog of cholesterol. Moreover, we show that the replacement of the residues
involved in the charged-pair located in the binding site results in the loss of
StAR activity, supporting a key role for these residues. Taken together, our
results are applicable to StAR functioning both in the mitochondrial
intermembrane space as well as outside the mitochondria.
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Secondary reference #1
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Title
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Analysis of the hamster adrenal star protein phosphorylation
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Authors
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A.Fleury,
A.P.Mathieu,
L.Ducharme,
P.Lavigne,
J.G.Lehoux.
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Ref.
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TO BE PUBLISHED ...
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