Lipoprotein-associated phospholipase A2 (Lp-PLA2) is one such protein with an important function in cardiovascular health, but its system of action on the phospholipid membrane was unknown. These lipoprotein particles are made up of a spherical layer of phospholipids surrounding a drop of fat and cholesterol esters. Over time, the phospholipids in this external layer ended up being oxidized, drawing in free radicals and further oxidation, which contributes to plaque accumulation and cardiovascular illness.
The group had actually formerly presented this principle of membrane-facilitated allosteric policy of PLA2 enzymes, however had till this point just studied enzymes that operate on phospholipid bilayers (as seen on cells and intracellular organelles). This research study verified that a comparable system might be utilized to assist in phospholipase action on phospholipid monolayers, such as those on lipoproteins.
Lp-PLA2 in its “closed” conformation (left) and “open” conformation (right) when bound to the phospholipid monolayer. Credit: UC San Diego Health Sciences
New simulations expose the mechanism of action and substrate uniqueness of lipoprotein-associated phospholipase A2, a biomarker for heart disease.
Membrane-associated proteins play an important function in a range of cellular processes, yet little is known about the membrane-association mechanism. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is one such protein with an essential function in cardiovascular health, however its mechanism of action on the phospholipid membrane was unidentified. To address this, researchers at University of California San Diego School of Medicine used advanced experimental and computational tools to show precisely how the enzyme connects with the membrane and extracts its specific substrates.
The findings were released on January 3, 2022, in the online concern of Proceedings of the National Academy of Sciences
Lp-PLA2 deals with lipoproteins in the blood stream, consisting of typical kinds like low- and high-density lipoprotein (LDL and HDL). These lipoprotein particles are made up of a spherical layer of phospholipids surrounding a drop of fat and cholesterol esters. Gradually, the phospholipids in this outer layer ended up being oxidized, attracting totally free radicals and additional oxidation, which contributes to plaque accumulation and heart disease.
Lp-PLA2 extracts these oxidized phospholipids from the lipoprotein membrane and releases their fats to be additional metabolized. Understanding exactly how this process works develops new chances for therapies against cardiovascular disease.
Schematic of a normal lipoprotein with a phospholipase bound to the outer phospholipid monolayer. Credit: UC San Diego Health Sciences.
” I am extremely happy that we were able to enter into much greater depth on how this enzyme works than ever before,” stated Edward A. Dennis, PhD, senior author of the study and Distinguished Professor of Pharmacology, Chemistry and Biochemistry at UC San Diego School of Medicine. “Using the current advances in lipidomics and computational molecular dynamics simulations, we got a photo which deserves a thousand words. We now have motion pictures that demonstrate how this enzyme works at the atomic level, and that need to help us find out methods to activate or suspend the enzyme as needed for health.”
This sophisticated approach exposed a particular peptide region including two alpha helices gotten in touch with a loop that functions as a gate to the enzymes active website. Generally, this gate is in a “closed” position, but when Lp-PLA2 binds to the phospholipid membrane, it goes through an allosteric conformational change that opens eviction and increases the volume of the active site.
Dennis team, led by very first author Varnavas D. Mouchlis, PhD, likewise revealed which oxidized phospholipid substrates Lp-PLA2 has the best affinity for. They even more recognized a binding pocket unique from known drug inhibitor binding pockets, which may serve as a brand-new target for future restorative drugs.
This study is the newest in a long line of work from the Dennis laboratory to develop a unifying theory on the function of phospholipases. The group had actually previously introduced this idea of membrane-facilitated allosteric guideline of PLA2 enzymes, however had up until this point just 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 assist in phospholipase action on phospholipid monolayers, such as those on lipoproteins.
” PLA2 enzymes have all sorts of essential functions in inflammation, digestion, brain health, and more, so its incredible to see this wide variety of enzymes all show a similar action strategy,” stated Dennis. “Weve been studying this superfamily of enzymes for nearly 50 years, so to lastly have this complete picture of how they work is truly satisfying, and the whole field advances.”
Recommendation: 3 January 2022, Proceedings of the National Academy of Sciences.DOI: 10.1073/ pnas.2102953119.
Co-authors consist of: Daiki Hayashi, Alexis M. Vazquez, Jian Cao and J. Andrew McCammon, all at UC San Diego.
