Author: Antonia Truta, Class of 2028

Lon protease is an important enzyme within the mitochondria’s inner membrane. This enzyme specifically regulates protein homeostasis, meaning it helps keep the protein levels within the cell balanced. The Lon protease acts by breaking down damaged or misfolded proteins that lack proper structure to function correctly and may harm the cell. Lon also degrades certain regulatory proteins whose levels need to be controlled for continued cell function.

In simple terms, this protein can be seen as functioning in three main steps: first, the Lon enzyme recognizes its target protein. Then, it uses ATP energy to unfold and pull the target into its central chamber. Finally, it cuts the protein into small fragments. While scientists know many of the proteins that Lon targets, it is still not clear how the Lon enzymes recognize and differentiate which of these proteins to cut.

This property of enzyme catalysts is crucial to its function in the cell. Enzymes are biological catalysts that speed up other reactions, often digestive or chemical reactions that relate to metabolism. The term “widely conserved” refers to proteins or molecules that are foundational to the processes of life due to their pivotal roles in energy or metabolic pathways of cells. For example, the Lon protease enzyme is commonly found in the mitochondria, a highly important ‘powerhouse’ which produces ATP energy for cells.

Recent research conducted by Melanie Cragan and colleagues in the Department of Biochemistry and Cell Biology of Stony Brook University has examined substrate recognition and cleavage of the Lon protease enzyme. The damaged proteins targeted by the Lon enzymes are marked with a special ‘degron’ sequence that signals them for destruction. This degron can be found at the start, end, or even inside the protein. However, researchers have found that the Lon enzyme’s cleavage, or cutting, pattern is independent of where the target protein’s degron was located, or how fast the degradation reaction took place. 

Overall, this study sheds more light on the inner workings of a widely conserved enzyme. By identifying the specific degron sequence, the scientists were able to predict Lon enzyme’s target proteins across many different types of bacteria, including E.coli. The researchers successfully identified 150 Lon substrates, about 4% of all predicted proteins. They also uncovered that the Lon enzyme prefers cutting after phenylalanine (Phe) chemical residues, and produces peptides of 7–35 amino acids. The discovery of this degron sequence helps identify the ways in which the Lon enzyme targets proteins, improving our understanding of protein homeostasis and cell regulation.

Works Cited

[1] Cragan, M., Puri, N., & Karzai, A. W. (2025). Substrate recognition and cleavage-site preferences of Lon Protease. Journal of Biological Chemistry, 301(4),108365. https://doi.org/10.1016/j.jbc.2025.108365. 

[2] https://www.jbc.org/article/S0021-9258(25)00214-5/fulltext