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J. Biol. Chem., Vol. 283, Issue 25, 17314-17323, June 20, 2008

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A Three-dimensional Homology Model of Lipid-free Apolipoprotein A-IV Using Cross-linking and Mass Spectrometry^*

Matthew R. Tubb, R. A. Gangani D. Silva, Jianwen Fang, Patrick Tso, and W. Sean Davidson¹

From the Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio 45237 and the Bioinformatics Core Facility, University of Kansas, Lawrence, Kansas 66045

Human apolipoprotein A-IV (apoA-IV) is a 46-kDa exchangeable plasma protein with many proposed functions. It is involved in chylomicron assembly and secretion, protection from atherosclerosis through a variety of mechanisms, and inhibition of food intake. There is little structural basis for these proposed functions due to the lack of a solved three-dimensional structure of the protein by x-ray crystallography or NMR. Based on previous studies, we hypothesized that lipid-free apoA-IV exists in a helical bundle, like other apolipoprotein family members and that regions near the N and C termini may interact. Utilizing a homobifunctional lysine cross-linking agent, we identified 21 intramolecular cross-links by mass spectrometry. These cross-links were used to constrain the building of a sequence threaded homology model using the I-TASSER server. Our results indicate that lipid-free apoA-IV does indeed exist as a complex helical bundle with the N and C termini in close proximity. This first structural model of lipid-free apoA-IV should prove useful for designing studies aimed at understanding how apoA-IV interacts with lipids and possibly with unknown protein partners.

Received for publication, January 2, 2008 , and in revised form, April 10, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL67093 and HL82734 (to W. S. D.). This work was also supported by a predoctoral fellowship from the Great Rivers Affiliate of the American Heart Association (to M. R. T.) and a University of Cincinnati graduate research fellowship (to M. R. T.). 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 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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