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J. Biol. Chem., Vol. 282, Issue 13, 9713-9721, March 30, 2007

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The Structure of Apolipoprotein A-II in Discoidal High Density Lipoproteins^*

R. A. Gangani D. Silva, Lumelle A. Schneeweis¹, Srinivasan C. Krishnan^¶, Xiuqi Zhang^||, Paul H. Axelsen¹, and W. Sean Davidson²

From the Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio 45237, the Departments of Pharmacology, Biochemistry, and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, the ^¶Mass Spectrometry Application Laboratory, Applied Biosystems, Framingham, Massachusetts 01701, and the ^||Department of Chemistry, University of Illinois, Chicago, Illinois 60607

It is well accepted that high levels of high density lipoproteins (HDL) reduce the risk of atherosclerosis in humans. Apolipoprotein A-I (apoA-I) and apoA-II are the first and second most common protein constituents of HDL. Unlike apoA-I, detailed structural models for apoA-II in HDL are not available. Here, we present a structural model of apoA-II in reconstituted HDL (rHDL) based on two well established experimental approaches: chemical cross-linking/mass spectrometry (MS) and internal reflection infrared spectroscopy. Homogeneous apoA-II rHDL were reacted with a cross-linking agent to link proximal lysine residues. Upon tryptic digestion, cross-linked peptides were identified by electrospray mass spectrometry. 14 cross-links were identified and confirmed by tandem mass spectrometry (MS/MS). Infrared spectroscopy indicated a beltlike molecular arrangement for apoA-II in which the protein helices wrap around the lipid bilayer rHDL disc. The cross-links were then evaluated on three potential belt arrangements. The data clearly refute a parallel model but support two antiparallel models, especially a "double hairpin" form. These models form the basis for understanding apoA-II structure in more complex HDL particles.

Received for publication, November 7, 2006 , and in revised form, January 25, 2007.

^* This work was supported in part by NHLBI, National Institutes of Health (NIH), Grant RO1-HL67093 (to W. S. D.) and an American Heart Association Ohio Valley Affiliate postdoctoral fellowship (to R. A. G. D. S.). 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.

¹ Supported by NIH Grant RO1-HL68186.

² To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, University of Cincinnati, 2120 Galbraith Rd., Cincinnati, OH 45237-0507. Tel.: 513-558-3707; Fax: 513-558-1312; E-mail: Sean.Davidson{at}UC.edu.

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