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J. Biol. Chem., Vol. 283, Issue 25, 17099-17106, June 20, 2008

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Identification of a Domain That Mediates Association of Platelet-activating Factor Acetylhydrolase with High Density Lipoprotein^*

Alison A. Gardner, Ethan C. Reichert, Matthew K. Topham, and Diana M. Stafforini¹

From the Huntsman Cancer Institute and Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84112

The plasma form of platelet-activating factor (PAF) acetylhydrolase (PAF-AH), also known as lipoprotein-associated phospholipase A₂ (Lp-PLA₂) inactivates potent lipid messengers such as PAF and modified phospholipids generated in settings of oxidant stress. In humans, PAF-AH circulates in blood in fully active form and associates with high and low density lipoproteins (HDL and LDL). Several studies suggest that the location of PAF-AH affects both the catalytic efficiency and the function of the enzyme in vivo. The distribution of PAF-AH among lipoproteins varies widely among mammals. Here, we report that mouse and human PAF-AHs associate with human HDL particles of different density. We made use of this observation in the development of a binding assay to identify domains required for association of human PAF-AH with human HDL. Sequence comparisons among species combined with domain-swapping and site-directed mutagenesis studies led us to the identification of C-terminal residues necessary for the association of human PAF-AH with human HDL. Interestingly, the region identified is not conserved among PAF-AHs, suggesting that PAF-AH interacts with HDL particles in a manner that is unique to each species. These findings contribute to our understanding of the mechanisms responsible for association of human PAF-AH with HDL and may facilitate future studies aimed at precisely determining the function of PAF-AH in each lipoprotein particle.

Received for publication, March 27, 2008 , and in revised form, April 22, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant HL35828 (to D. M. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ To whom correspondence should be addressed: Huntsman Cancer Inst., 2000 Circle of Hope, University of Utah, Salt Lake City, UT 84112-5550. Tel.: 801-585-3402; Fax: 801-585-0101; E-mail: diana.stafforini{at}hci.utah.edu.

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