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This advanced approach revealed a specific peptide region consisting of two alpha helices connected with a loop that acts as a gate to the enzyme’s active site. Typically, this gate is in a “closed” position, but when Lp-PLA2 binds to the phospholipid membrane, it undergoes an allosteric conformational change that opens the gate and increases the volume of the active site.
Dennis’ team, led by first author Varnavas D. Mouchlis, Ph.D., also showed which oxidized phospholipid substrates Lp-PLA2 has the greatest affinity for. They further identified a binding pocket distinct from known drug inhibitor binding pockets, which may serve as a new target for future therapeutic drugs.
This study is the latest in a long line of work from the Dennis lab to develop a unifying theory on the function of phospholipases. The group had previously introduced this concept of membrane-facilitated allosteric regulation of PLA2 enzymes, but had until this point only studied enzymes that function on phospholipid bilayers (as seen on cells and intracellular organelles). This study confirmed that a similar mechanism could be used to facilitate phospholipase action on phospholipid monolayers, such as those on lipoproteins.
“PLA2 enzymes have all sorts of important functions in inflammation, digestion, brain health, and more, so it’s amazing to see this wide variety of enzymes all show a similar action strategy,” said Dennis. “We’ve been studying this superfamily of enzymes for almost 50 years, so to finally have this complete picture of how they work is really satisfying, and the whole field advances.”
Co-authors include: Daiki Hayashi, Alexis M. Vazquez, Jian Cao and J. Andrew McCammon, all at UC San Diego.
Lipoprotein-associated phospholipase A: A paradigm for allosteric regulation by membranes, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2102953119.
Computer model of blood enzyme may lead to new drugs for cardiovascular disease (2022, January 3)
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