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J. Biol. Chem., Vol. 278, Issue 46, 45563-45569, November 14, 2003

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The Potential of Fluorescent and Spin-labeled Steroid Analogs to Mimic Natural Cholesterol^*

Holger A. Scheidt, Peter Müller, Andreas Herrmann, and Daniel Huster¶

From the Junior Research Group, Solid-state NMR Studies of Membrane-associated Proteins, Biotechnological-Biomedical Center/Institute of Medical Physics and Biophysics, University of Leipzig, Liebigstr. 27, D-04103 Leipzig, Germany and the Humboldt-University Berlin, Institute of Biology/Biophysics, Invalidenstr. 42, D-10115 Berlin, Germany

Cholesterol analogs are often used to investigate lipid trafficking and membrane organization of native cholesterol. Here, the potential of various spin (doxyl moiety) and fluorescent (7-nitrobenz-2-oxa-1,3-diazol-4-yl (NBD) group) labeled cholesterol analogs as well as of fluorescent cholestatrienol and the naturally occurring dehydroergosterol to mimic the unique properties of native cholesterol in lipid membranes was studied in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membranes by electron paramagnetic resonance, nuclear magnetic resonance, and fluorescence spectroscopy. As cholesterol, all analogs undergo fluctuating motions of large amplitude parallel to the bilayer normal. Native cholesterol keeps a strict orientation in the membrane with the long axis parallel to the bilayer normal. Depending on the chemical modification or the position of the label, cholesterol analogs may adopt an "up-side-down" orientation in the membrane or may even fluctuate between "upright" and up-side-down orientation by rotational motions about the short axis not typical for native cholesterol. Those analogs are not able to induce a comparable condensation of phospholipid membranes as known for native cholesterol revealed by ²H nuclear magnetic resonance. However, cholesterol-induced lipid condensation is one of the key properties of native cholesterol, and, therefore, a well suited parameter to assess the potential of steroid analogs to mimic cholesterol. The study points to extreme caution when studying cholesterol behavior by the respective analogs. Among seven analogs investigated, only a spin-labeled cholesterol with the doxyl group at the end of the acyl chain and the fluorophore cholestatrienol mimic cholesterol satisfactorily. Dehydroergosterol has a similar upright orientation as cholesterol and could be used at low concentration (about 1 mol %), at which its lower potential to enhance lipid packing density does not perturb membrane organization.

Received for publication, April 7, 2003 , and in revised form, August 21, 2003.

^* This work was supported by the Deutsche Forschungsgemeinschaft. The Junior Research Group is funded by the Saxon State Ministry of Higher Education, Research and Culture. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 49-341-97-15706; Fax: 49-341-97-15709; E-mail: husd{at}medizin.uni-leipzig.de.

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