A new study entitled “Ambidextrous binding of cell and membrane bilayers by soluble matrix metalloproteinase-12” published in Nature Communications reports on the structure of the matrix metallo-proteinase-12 (MMP-12), a key enzyme in inflammatory diseases and cancer, and how its complementary structure allows the enzyme to associate with membranes of live cells, which ultimately leads to its internalization and modulation of cellular transcriptional responses. The study was published in the journal Nature Communications.
Matrix metallo-proteinase-12 (MMP-12) is a key enzyme for macrophages’ responses to infections and regulation of inflammation. Notably, in viral infections MMP-12 is capable of reaching virus-infected cells nuclei and activates a transcriptional program against virus infection. Additionally, MMP-12 impacts inflammatory diseases, such as chronic obstructive pulmonary disease and arthritis, cancer and heart disease. Therefore, understanding its mechanism of action is crucial for potential therapeutic interventions.
In this study, a team of researchers at the University of Missouri aimed to determine whether MMP-12 is active around cells, specifically, if the enzyme is capable of binding to the membrane of living cells and thus understand how it can enter and move through cells.
The team fused MMP-12 with a fluorescent substance which allowed the researchers to track MMP-12 interaction with cell membranes at a sub-microscopic scale, using a technique called parametric nuclear magnetic resonance (NMR). The authors found that indeed MMP-12 binds to plasma and intracellular membranes, via its catalytic domain composed of two complementary structures, found in opposite directions. This allows a continuous localization of MMP-12 close to membranes, therefore enhancing its activity in these sites, which ultimately allows aces to inside cells and trafficking to the nucleus.
Steven Van Doren, a professor in the MU Department of Biochemistry noted, “We know that MMP12 enzymes play important roles in fighting bacterial and viral infections and fighting arthritis. The more we understand these enzymes, the closer we come to learning how to use these enzymes more effectively to fight diseases while preventing them from causing damage when they act inappropriately. This illustrates the importance of basic scientific research when looking to solve large, practical problems. One next step is to determine how these enzymes get through the cell. Understanding that mechanism will tell us much about how these enzymes work.”