Chemists use technology to decode language of lipid-protein interaction

Membrane protein samples are infused into the mass spectrometry using nanoflow electrospray ionization (nESI). In this artwork, free and lipid bound membrane proteins are emerging from droplets in the nESI process prior to entering the mass spectrometer.

Image: Laganowsky Laboratory, Texas A&M University

Technology has a massive impact on our day-to-day lives, right down to the cellular level within our own bodies. Texas A&M University chemists are using it to determine how lipids talk to each other when they interact with membrane proteins, one of the primary targets for drug discovery and potential treatments for any number of different diseases.

By capitalizing on their technological expertise to “see” membrane proteins as they interact with different lipids, Texas A&M chemist Arthur Laganowsky’s research group has discovered compelling evidence that these proteins may be capable of recruiting their own lipid microenvironments through allostery, a biological phenomenon first observed in the 1900s and identified in numerous biological processes, including cellular signaling, transcriptional control and disease.

Laganowsky is an assistant professor in the Department of Chemistry, College of Science. His team’s work, which was published on March 5 in Proceedings of the National Academy of Sciences and led by Texas A&M chemistry postdoctoral researchers Christopher Boone and John W. Patrick, shows that allostery extends to lipid-membrane protein interactions, enabling these proteins to alter their remote binding sites to accept lipids of different types and opening up new possibilities for pharmaceutical drug design and delivery.

Protective membranes exist on the surface of all living cells and contain many of our cells’ most important proteins, many of which have unique and specialized functions, such as safeguarding the cargo going into and out of the cell that is necessary for cell survival. These membranes are largely composed of lipids, which themselves play key roles in maintaining membrane integrity and ensuring that these specialized membrane proteins function properly.

“From this work and our previous work, it is becoming increasingly clear that membrane proteins are exquisitely sensitive to the chemistry of the lipid,” Laganowsky says. “Given that lipid composition differs throughout the organs of the body, understanding how the lipid environment in these areas influences protein structure will be critical to opening new possibilities for pharmaceutical drugs designed to affect how these lipids bind with one another.”

Membrane proteins represent one of the most important targets for pharmaceutical drug discovery, with a staggering 60 percent of drugs on the current market targeting them for their integral role in cellular processes. The crucial role of lipids in the folding, structure and function of membrane proteins is emerging through multiple research reports and channels—findings that are uncovering the intimate roles lipid-protein interactions play in controlling protein structure and function.

“In a cell, molecular interactions with molecules are exploited to carry out cellular processes,” Laganowsky explains. “For example, when you eat a chili pepper, you feel a hot sensation as a result of a molecule in the pepper binding to a specific membrane protein that, in turn, elicits this response. In a similar fashion, our study has demonstrated that the membrane protein can influence its surrounding lipid environment, and this environment may influence, for example, how molecules are sensed.”

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