Author: Sean Krivitsky, Class of 2026

Figure 1. Painting representation of large biological molecules found within the bloodstream, including lipoproteins, which store triglycerides, and antibodies

The metabolism of various lipids, such as triglycerides, within the body plays an incredibly important role in providing energy for crucial cells, such as those contained within the heart and other muscles. These metabolic processes are primarily catalyzed by metabolic enzymes, one of which is lipoprotein lipase (LPL), and dysregulation of these enzymes is strongly implicated in severe metabolic disorders that can also increase risk for cardiovascular disease. As a result, some of these metabolic enzymes have evolved to self-assemble into large filamentous polymers, which are capable of either upregulating or downregulating their capacity to catalyze enzymatic reactions. 

In the case of LPL, it is stored in inactivated filaments inside cellular compartments until they are signaled to be released from the cell into the bloodstream, disassemble into its functional form, and catalyze the metabolism of triglycerides. Thus, forming these ordered filaments is crucial to its maintenance of this tightly regulated process. Despite its importance, the exact organization of these filaments in the cell and the mechanism by which filamentation inactivates this enzyme has yet to be elucidated.

Therefore, recently-appointed Stony Brook University Professor Dr. Kathrynn Gunn sought to tackle this knowledge gap. Using state-of-the-art methods in electron microscopy, Dr. Gunn solved the structure of LPL filaments by single-molecule cryo-electron microscopy (cryo-EM), and identified its architecture and organization within cellular compartments by cryo-electron tomography, a technique that allows for 3D reconstruction on a larger scale than cryo-EM. This work revealed that cellular compartments, called vesicles, contain LPL filaments organized into either a tightly packed structure filling the entire volume of the vesicles, or closely associated with the inner vesicle membrane through interactions with a membrane protein. Furthermore, solving the structure of these LPL filaments also demonstrated that individual LPL pairs organize with one another within the larger filament structure such that they occlude one another’s catalytic sites, inactivating the enzyme until the filament can disassemble in the bloodstream.

This work provides important insights into this newly discovered mechanism of metabolic enzyme regulation, demonstrating how different organizations within protein filaments can have differing effects of an enzyme’s catalytic activity. With this newfound knowledge of LPL activity regulation, a deeper path for exploration of lipid metabolism, metabolic pathway regulation, and therapeutic relevance of this discovery has been opened.

Work’s Cited

[1] Gunn, K. H., Wheless, A., Calcraft, T., Kreutzberger, M., El-Houshy, K., Egelman, E. H., Rosenthal, P. B., & Neher, S. B. (2025). Cryogenic Electron Tomography reveals Helical Organization of lipoprotein lipase in storage vesicles. Science Advances, 11(32). https://doi.org/10.1126/sciadv.adx8711 

[2] Image retrieved from: https://commons.wikimedia.org/wiki/File:2005_Biosites-blood-plasma.tif