Assembly, activation and function of JAMM/MPN deubiquitinating complexes

The small protein ubiquitin can alter the fate of a cell’s life. It is attached to other proteins as a tag that carries specific signals and important instructions. Enzymes that perform the protein tagging process (ubiquitylation) are called ligases and those that remove the ubiquitin tag are called deubiquitylases (DUBs). The cell has evolved in many ways to control the activity of DUBs because these are often mutated in cancer, neurodegeneration and autoimmune disease.

I’m interested in a specific DUB family called JAMM/MPN. These proteins often do not act alone, but interact and form large complexes with other regulatory proteins. I want to understand how one such DUB, BRCC36, forms large molecular machines and how it becomes active when the cell requires its services to remove ubiquitin tags. This is important because BRCC36 serves as a safeguard to ensure that immune signals are passed on to clear a viral infection. On other occasions, BRCC36 provides a sitting platform for proteins to repair a damaged strand of DNA.

An important aspect of my research is to identify small molecules that can help us understand how BRCC36 works and perhaps provide a starting point for future therapeutic agents.