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J. Biol. Chem., Vol. 278, Issue 29, 27199-27207, July 18, 2003

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The Spatial Organization of Apolipoprotein A-I on the Edge of Discoidal High Density Lipoprotein Particles

A MASS SPECTROMETRY STUDY^*

W. Sean Davidson   and George M. Hilliard ¶

From the Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0529 and the ^¶Department of Molecular Sciences and Center of Excellence in Genomics and Bioinformatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163

The three-dimensional structure of human apoA-I on nascent, discoidal HDL particles has been debated extensively over the past 25 years. Recent evidence has demonstrated that the -helical domains of apoA-I are arranged in a belt-like orientation with the long axis of the helices perpendicular to the phospholipid acyl chains on the disc edge. However, experimental information on the spatial relationships between apoA-I molecules on the disc is lacking. To address this issue, we have taken advantage of recent advances in mass spectrometry technology combined with cleavable cross-linking chemistry to derive a set of distance constraints suitable for testing apoA-I structural models. We generated highly homogeneous, reconstituted HDL particles containing two molecules of apoA-I. These were treated with a thiol-cleavable cross-linking agent, which covalently joined Lys residues in close proximity within or between molecules of apoA-I in the disc. The cross-linked discs were then exhaustively trypsinized to generate a discrete population of peptides. The resulting peptides were analyzed by liquid chromatography/mass spectrometry before and after cleavage of the cross-links, and resulting peaks were identified based on the theoretical tryptic cleavage of apoA-I. We identified at least 8 intramolecular and 7 intermolecular cross-links in the particle. The distance constraints are used to analyze three current models of apoA-I structure. The results strongly support the presence of the salt-bridge interactions that were predicted to occur in the "double belt" model of apoA-I, but a helical hairpin model containing the same salt-bridge docking interface is also consistent with the data.

Received for publication, March 18, 2003 , and in revised form, April 28, 2003.

^* This work was supported in part by RO1 Grants HL62542 and HL67093 from NHLBI, National Institutes of Health (to W. S. D.). 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.

An Established Investigator of the American Heart Association. To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0529. Tel.: 513-558-3707; Fax: 513-558-2289; E-mail: Sean.Davidson{at}UC.edu.

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