Scientists Discover New Mechanism for Protein Degradation in Cells, Potentially Leading to Treatment Breakthroughs
Scientists from Harvard Medical School have made a groundbreaking discovery in understanding how cells degrade unneeded proteins, a finding that could have significant implications for the treatment of conditions caused by protein imbalances in cells. The researchers identified a protein called midnolin that plays a key role in degrading short-lived nuclear proteins that support brain functioning, immune response, and development. Midnolin is responsible for grabbing these proteins and pulling them into the cellular waste-disposal system, known as the proteasome, where they are destroyed. The findings of the study were recently published in the journal Science.
For decades, scientists have been puzzled by the mechanism behind the degradation and removal of these essential proteins. This new discovery sheds light on this molecular mystery and opens up possibilities for targeted treatments. These short-lived proteins control gene expression and perform critical roles within cells, but once they have fulfilled their purpose, they are swiftly degraded. By understanding how midnolin facilitates this degradation process, researchers may be able to manipulate protein levels to correct dysfunctions related to brain function, the immune system, and development.
The research team employed advanced protein and genetic analyses to identify midnolin as the protein responsible for breaking down short-lived nuclear proteins. Further experiments revealed that midnolin may also be involved in breaking down hundreds of other transcription factors in the nucleus. The scientists used a machine learning tool called AlphaFold to predict protein structures and combined these results with laboratory experiments to gain a better understanding of how midnolin targets and degrades proteins. It was discovered that midnolin possesses a “Catch domain” that functions as a protein-grabbing region, allowing it to feed proteins directly into the proteasome for degradation.
The translational potential of this discovery is significant. Controlling protein levels by targeting the midnolin-proteasome pathway could modulate gene expression and associated processes in the body. The researchers anticipate that this pathway could be harnessed to develop therapies for various disorders and diseases, including neurological and psychiatric conditions, certain cancers, and other diseases caused by deregulated protein degradation. By understanding the mechanism at a deeper level, scientists hope to develop treatments that can specifically degrade proteins of interest.
In the short term, the researchers plan to conduct structural studies to gain a better understanding of the fine-scale details of how midnolin captures and degrades proteins. They also aim to explore the role of midnolin in different cells and stages of development by creating mice that lack the protein. The researchers are excited about the potential of their findings and the future possibilities they hold in the realm of protein degradation and targeted therapies.
The study was funded by the Damon Runyon Cancer Research Foundation, the National Science Foundation, and the National Institutes of Health (NIH). The researchers are hopeful that their discoveries will pave the way for new treatment approaches and improved outcomes for patients with conditions affected by protein imbalances in cells. Further research and development will be carried out to fully exploit the potential of the midnolin-proteasome pathway and its applications in healthcare.