Lipoprotein-associated phospholipase A <sub>2</sub> : A paradigm for allosteric regulation by membranes
Varnavas D. Mouchlis, Daiki Hayashi, Alexis M. Vasquez, Jian Cao, J. Andrew McCammon, Edward A. Dennis
Abstract
Significance Lp-PLA 2 is a physiologically important human enzyme and an inflammatory biomarker for assessing risk factors associated with cardiovascular diseases. It is associated with low- and high-density lipoproteins in human plasma and acts on the outside of the phospholipid monolayer that coats these particles, in stark contrast to traditional PLA 2 enzymes that act on bilayer membranes. This study addresses the allosteric activation of Lp-PLA 2 by phospholipid monolayers and membranes, its precise selectivity and specificity for particular oxidized and short acyl-chain phospholipid substrates not previously possible. Of particular importance, this work identifies and confirms by site-directed mutagenesis a phospholipid head-group binding pocket distinct from known drug inhibitor binding pockets that informs us about Lp-PLA 2 ’s mechanism of action and creates opportunities for additional therapeutic approaches.