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Papers In Press, published online ahead of print December 1, 2006
J. Lipid Res., doi:10.1194/jlr.M600232-JLR200

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Journal of Lipid Research, Vol. 47, 2614-2630, December 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Modeling the structure of the StART domains of MLN64 and StAR proteins in complex with cholesterol^1,

Marta Murcia^*, José D. Faráldo-Gómez, Frederick R. Maxfield and Benoît Roux^2,

^* Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY 10021
Department of Biochemistry and Molecular Biology and Institute for Molecular Pediatric Sciences, Center for Integrative Sciences, University of Chicago, Chicago IL 60637
Department of Biochemistry, Weill Medical College of Cornell University, New York, NY 10021

¹ Coordinates of both MNL64- and StAR-StART domains in complex with cholesterol have been deposited in the Protein Data Bank (accession code 2I92 and 2I93 respectively).

The online version of this article (available at http://www.jlr.org) contains supplemental data in the form of movies and seven figures.

Published, JLR Papers in Press, September 21, 2006.

² To whom correspondence should be addressed. e-mail: roux{at}uchicago.edu

Steroidogenic acute regulatory protein-related lipid transfer (StART) domains are ubiquitously involved in intracellular lipid transport and metabolism and other cell-signaling events. In this work, we use a flexible docking algorithm, comparative modeling, and molecular dynamics (MD) simulations to generate plausible three-dimensional atomic models of the StART domains of human metastatic lymph node 64 (MLN64) and steroidogenic acute regulatory protein (StAR) proteins in complex with cholesterol. Our results show that cholesterol can adopt a similar conformation in the binding cavity in both cases and that the main contribution to the protein-ligand interaction energy derives from hydrophobic contacts. However, hydrogen-bonding and water-mediated interactions appear to be important in the fine-tuning of the binding affinity and the position of the ligand. To gain insights into the mechanism of binding, we carried out steered MD simulations in which cholesterol was gradually extracted from within the StAR model. These simulations indicate that a transient opening of loop 1 may be sufficient for uptake and release, and they also reveal a pathway of intermediate states involving residues known to be crucial for StAR activity. Based on these observations, we suggest specific mutagenesis targets for binding studies of cholesterol and its derivatives that could improve our understanding of the structural determinants for ligand binding by sterol carrier proteins.

Supplementary key words steroidogenic acute regulatory protein • steroidogenic acute regulatory protein-related lipid transfer • metastatic lymph node 64 • docking • homology modeling • generalized-Born • binding • molecular dynamics • steered molecular dynamics • cholesterol release

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