The mechanism degrades short-lived proteins that support brain and immune functions.
Short-lived proteins control gene expression in cells to carry out a number of vital tasks, from helping the brain form connections to helping the body mount an immune defense. These proteins are made in the nucleus and are quickly destroyed once they’ve done their job.Despite their importance, the process by which these proteins get broken down and removed from cells once they are no longer needed has eluded scientists for decades — until now.
- Scientists have discovered a previously unknown mechanism by which cells break down proteins that are no longer needed.
- These proteins are short-lived and modulate genes that support important neural, immune, and developmental processes.
- The mechanism could inform the design of therapies to treat conditions that arise when cells make too much or too little of a protein.
To investigate the turnover mechanism, researchers began with two familiar transcription factors: Fos, studied extensively for its role in learning and memory, and EGR1, which is involved in cell division and survival. Using sophisticated protein and genetic analyses, the researchers homed in on midnolin as a protein that helps break down both transcription factors. Follow-up experiments revealed that in addition to Fos and EGR1, midnolin may also be involved in breaking down hundreds of other transcription factors in the nucleus.
The research team was surprised and skeptical about their results so, for confirmation, they wanted to figure out exactly how midnolin targets and degrades so many different proteins.
With the aid of a machine learning tool called AlphaFold that predicts protein structures, plus results from a series of lab experiments, the team was able to flesh out the details of the mechanism. They established that midnolin has a “Catch domain”—a region of the protein that grabs other proteins and feeds them directly into the proteasome, where they are broken down. This Catch domain is composed of two separate regions linked by amino acids that grab a relatively unstructured region of a protein, thus allowing midnolin to capture many different types of proteins.
“The most exciting aspect of this study is that we now understand a new general, ubiquitination-independent mechanism that degrades proteins,” said co-senior author Stephen Elledge, the professor of genetics and medicine at HMS and Brigham and Women’s Hospital.
In the short term, the researchers want to delve deeper into the mechanism they discovered. They are planning structural studies to better understand the fine-scale details of how midnolin captures and degrades proteins. They are also making mice that lack midnolin to understand the protein’s role in different cells and stages of development.
The team says the findings, published in Science, have great translational potential. The results may offer a pathway that researchers can harness to control levels of transcription factors, thus modulating gene expression, and in turn, associated processes in the body.
