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J. Biol. Chem., Vol. 282, Issue 39, 28385-28394, September 28, 2007

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Modulation of Apolipoprotein A-IV Lipid Binding by an Interaction between the N and C Termini^*

Matthew R. Tubb, R. A. Gangani D. Silva, Kevin J. Pearson, Patrick Tso, Min Liu, and W. Sean Davidson¹

From the Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio 45237 and the Laboratory of Experimental Gerontology, NIA, National Institutes of Health, Baltimore, Maryland 21224

Apolipoprotein A-IV (apoA-IV) is a 376-amino acid exchangeable apolipoprotein made in the small intestine of humans. Although it has many proposed roles in vascular disease, satiety, and chylomicron metabolism, there is no known structural basis for these functions. The ability to associate with lipids may be a key step in apoA-IV functionality. We recently identified a single amino acid, Phe³³⁴, which seems to inhibit the lipid binding capability of apoA-IV. We also found that an intact N terminus was necessary for increased lipid binding of Phe³³⁴ mutants. Here, we identify Trp¹² and Phe¹⁵ as the N-terminal amino acids required for the fast lipid binding seen with the F334A mutant. Furthermore, we found that individual disruption of putative amphipathic -helices 3–11 had little effect on lipid binding, suggesting that the N terminus of apoA-IV may be the operational site for initial lipid binding. We also provide three independent pieces of experimental evidence supporting a direct intramolecular interaction between sequences near amino acids 12/15 and 334. This interaction could represent a unique "switch" mechanism by which apoA-IV changes lipid avidity in vivo.

Received for publication, May 16, 2007 , and in revised form, August 8, 2007.

^* This work was supported by National Institutes of Health Grants HL67093 and HL82734 (to W. S. D.), two predoctoral fellowships from the Ohio Valley Affiliate of the American Heart Association (to M. R. T. and K. J. P.), 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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