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J. Biol. Chem., Vol. 280, Issue 46, 38576-38582, November 18, 2005

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Specific Sequences in the N and C Termini of Apolipoprotein A-IV Modulate Its Conformation and Lipid Association^*

Kevin Pearson1, Matthew R. Tubb, Masafumi Tanaka, Xiu Qi Zhang¶, Patrick Tso, Richard B. Weinberg||, and W. Sean Davidson2

From the Department of Pathology and Laboratory Medicine, The University of Cincinnati, Cincinnati, Ohio 45237, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, ^¶Department of Chemistry, University of Illinois, Chicago, Illinois 60607, and ^||Departments of Internal Medicine and Physiology and Pharmacology, Wake Forest University, Winston-Salem, North Carolina 27157

Apolipoprotein (apoA-IV) is a 376-residue exchangeable apolipoprotein that may play a number of important roles in lipid metabolism, including chylomicron assembly, reverse cholesterol transport, and appetite regulation. In vivo, apoA-IV exists in both lipid-poor and lipid-associated forms, and the balance between these states may determine its function. We examined the structural elements that modulate apoA-IV lipid binding by producing a series of deletion mutants and determining their ability to interact with phospholipid liposomes. We found that the deletion of residues 333–343 strongly increased the lipid association rate versus native apoA-IV. Additional mutagenesis revealed that two phenylalanine residues at positions 334 and 335 mediated this lipid binding inhibitory effect. We also observed that residues 11–20 in the N terminus were required for the enhanced lipid affinity induced by deletion of the C-terminal sequence. We propose a structural model in which these sequences can modulate the conformation and lipid affinity of apoA-IV.

Received for publication, June 22, 2005 , and in revised form, September 12, 2005.

^* This work was supported by National Institutes of Health Grants HL67093, HL62542 (to W. S. D.), and HL30897 (to R. B. W.). 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 a predoctoral fellowship from the Ohio Valley affiliate of the American Heart Association.

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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