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J. Biol. Chem., Vol. 283, Issue 23, 15779-15788, June 6, 2008

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The Specific Amino Acid Sequence between Helices 7 and 8 Influences the Binding Specificity of Human Apolipoprotein A-I for High Density Lipoprotein (HDL) Subclasses

A POTENTIAL FOR HDL PREFERENTIAL GENERATION^*

Ronald Carnemolla¹, Xuefeng Ren^¶1, Tapan K. Biswas, Stephen C. Meredith, Catherine A. Reardon, Jianjun Wang^¶, and Godfrey S. Getz²

From the Department of Pathology and the Committee of Molecular Metabolism and Nutrition, The University of Chicago, Chicago, Illinois 60637 and the ^¶Department of Biochemistry and Molecular Biology, Wayne State University, Detroit, Michigan 48201

Humans have two major high density lipoprotein (HDL) sub-fractions, HDL₂ and HDL₃, whereas mice have a monodisperse HDL profile. Epidemiological evidence has suggested that HDL₂ is more atheroprotective; however, currently there is no direct experimental evidence to support this postulate. The amino acid sequence of apoA-I is a primary determinant of HDL subclass formation. The majority of the -helical repeats in human apoA-I are proline-punctuated. A notable exception is the boundary between helices 7 and 8, which is located in the transitional segment between the stable N-terminal domain and the C-terminal hydrophobic domain. In this study we ask whether the substitution of a proline-containing sequence (PCS) separating other helices in human apoA-I for the non-proline-containing sequence (NPCS) between helices 7 and 8 (residues 184–190) influences HDL subclass association. The human apoA-I mutant with PCS2 replacing NPCS preferentially bound to HDL₂. In contrast, the mutant where PCS3 replaced NPCS preferentially associated with HDL₃. Thus, the specific amino acid sequence between helices 7 and 8 influences HDL subclass association. The wild-type and mutant proteins exhibited similar physicochemical properties except that the two mutants displayed greater lipid-associated stability versus wild-type human apoA-I. These results focus new attention on the influence of the boundary between helices 7 and 8 on the properties of apoA-I. The expression of these mutants in mice may result in the preferential generation of HDL₂ or HDL₃ and allow us to examine experimentally the anti-atherogenicity of the HDL subclasses.

Received for publication, December 17, 2007 , and in revised form, April 1, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants 5T32 HL07237 (a Cardiovascular Pathophysiology and Biochemistry Training Program grant to R. C.), R01 HL68661 (to G. S. G.), R01 NS042852 (to S. C. M.), and R01 HL076620 (to J. W.). This work was also supported by Alzheimer's Association Grant IIRG-06-27794 (to S. C. M.). 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 These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pathology, The University of Chicago, MC 1089, 5841 S. Maryland Ave., Chicago, IL 60637. E-mail: g-getz{at}uchicago.edu.

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