Computer Model of Blood Enzyme

Membrane-associated proteins play a vital role in a variety of cellular processes, yet little is known about the membrane-association mechanism. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is one such protein with an important role in cardiovascular health, but its mechanism of action on the phospholipid membrane was unknown. To address this, researchers at University of California San Diego School of Medicine used state-of-the-art experimental and computational tools to show exactly how the enzyme interacts with the membrane and extracts its specific substrates.

The findings are publishing Jan. 3, 2022 in the online issue of Proceedings of the National Academy of Sciences.

Lp-PLA2 works on lipoproteins in the bloodstream, including common forms 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. Over time, the phospholipids in this outer layer become oxidized, attracting free radicals and further oxidation, which contributes to plaque buildup and cardiovascular disease.

Lp-PLA2 extracts these oxidized phospholipids from the lipoprotein membrane and releases their fatty acids to be further metabolized. Understanding exactly how this process works creates new opportunities for therapeutics against cardiovascular disease.

"I am very pleased that we were able to go into much greater depth on how this enzyme works than ever before," said 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 latest advances in lipidomics and computational molecular dynamics simulations, we got a picture which is worth a thousand words. We now have movies that show how this enzyme works at the atomic level, and that should help us figure out ways to activate or inactivate the enzyme as necessary for health."

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, PhD, 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-related phospholipase A: a paradigm of membrane-based allosteric regulation.
Proceedings of the National Academy of Sciences, 2022. doi: 10.1073 / pnas.2102953119

Most Popular Now

Health Fabric and Sandwell Council Secur…

Digital health company Health Fabric is preparing to work with Sandwell Council after learning that it has secured support from The Healthy Ageing Challenge. The company will work with public health...

Philips Highlights AI-Powered Precision …

Royal Philips (NYSE: PHG, AEX: PHIA), a global leader in health technology, showcases its award-winning AI-powered systems and solutions debuting at the European Congress of Radiology (ECR, July 13-17, Vienna...

Could a Computer Diagnose Alzheimer's Di…

It takes a lot of time - and money - to diagnose Alzheimer's disease. After running lengthy in-person neuropsychological exams, clinicians have to transcribe, review, and analyze every response in...

Siemens Healthineers Accelerates and Imp…

Siemens Healthineers presents functionalities powered by Artificial Intelligence (AI) that accelerate and improve Magnetic Resonance Imaging (MRI). The quality of MR imaging is defined by the trade-off between scan time...

Building the Right Foundations to Delive…

Opinion Article by Gary Birks, Gary Birks, General Manager, UK and Ireland, Orion Health. The latest strategy for health and care IT looks to build on what has been achieved over...

Using Technology to Support Primary Care

Opinion Article by Paul Bensley, Managing Director of Primary Care Cloud Telephony Specialist X-on. It is good to see the publication of this strategy [A plan for digital health and social...

A Machine Learning Model to Predict Immu…

Immunotherapy is a new cancer treatment that activates the body's immune system to fight against cancer cells without using chemotherapy or radiotherapy. It has fewer side effects than conventional anticancer...

Virtual Reality App Trial Shown to Reduc…

Results from a University of Otago, Christchurch trial suggest fresh hope for the estimated one-in-twelve people worldwide suffering from a fear of flying, needles, heights, spiders and dogs. The trial, led...

Two Leading CIOs Join the Highland Marke…

Two of the NHS' most dynamic chief information officers have joined Highland Marketing’s advisory board of NHS IT professionals and health tech industry experts. Ian Hogan, a CIO at the Northern...

Teaching AI to Ask Clinical Questions

Physicians often query a patient's electronic health record for information that helps them make treatment decisions, but the cumbersome nature of these records hampers the process. Research has shown that...

AI Analyses Neuron Changes to Detect whe…

A research group from Nagoya University in Japan has developed an artificial intelligence (AI) for analyzing cell images that uses machine learning to predict the therapeutic effect of drugs. Called...

MIT Engineers Develop Stickers that can …

Ultrasound imaging is a safe and noninvasive window into the body’s workings, providing clinicians with live images of a patient’s internal organs. To capture these images, trained technicians manipulate ultrasound...