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J. Biol. Chem., Vol. 282, Issue 21, 15484-15489, May 25, 2007

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The C Terminus of Apolipoprotein A-V Modulates Lipid-binding Activity^*

Jennifer A. Beckstead, Kasuen Wong, Vinita Gupta, Chung-Ping L. Wan^¶, Victoria R. Cook^||, Richard B. Weinberg^||**, Paul M. M. Weers^¶, and Robert O. Ryan¹

From the Center for Prevention of Obesity, Diabetes, and Cardiovascular Disease, Children's Hospital Oakland Research Institute, Oakland, California 94609, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California 94720, ^¶Department of Chemistry and Biochemistry, California State University, Long Beach, California 90840, Departments of ^||Internal Medicine and ^**Physiology and Pharmacology, Wake Forest University School of Medicine, Winston Salem, North Carolina 27157

Human apolipoprotein A-V (apoA-V) is a potent modulator of plasma triacylglycerol (TG) levels. To probe different regions of this 343-amino-acid protein, four single Trp apoA-V variants were prepared. The variant with a Trp at position 325, distal to the tetraproline sequence at residues 293–296, displayed an 11-nm blue shift in wavelength of maximum fluorescence emission upon lipid association. To evaluate the structural and functional role of this C-terminal segment, a truncated apoA-V comprising amino acids 1–292 was generated. Far UV circular dichroism spectra of full-length apoA-V and apoA-V-(1–292) were similar, with 50% -helix content. In guanidine HCl denaturation experiments, both full-length and truncated apoA-V yielded biphasic profiles consistent with the presence of two structural domains. The denaturation profile of the lower stability component (but not the higher stability component) was affected by truncation. Truncated apoA-V displayed an attenuated ability to solubilize L--dimyristoylphosphatidylcholine phospholipid vesicles compared with full-length apoA-V, whereas a peptide corresponding to the deleted C-terminal segment displayed markedly enhanced kinetics. The data support the concept that the C-terminal region is not required for apoA-V to adopt a folded protein structure, yet functions to modulate apoA-V lipid-binding activity; therefore, this concept may be relevant to the mechanism whereby apoA-V influences plasma TG levels.

Received for publication, December 26, 2006 , and in revised form, March 2, 2007.

^* This work was supported by National Institutes of Health Grants HL 73061 (to R. O. R.), HL 077135 (to P. M. M. W.), and HL 30897 (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 To whom correspondence should be addressed: CHORI, 5700 Martin Luther King Jr. Way, Oakland, CA 94609. Tel.: 510-450-7645; Fax: 510-450-7910; E-mail: rryan{at}chori.org.

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