Pathways of Ubiquitin Mediated Degradation
Proteins in the cell are principally degraded via the ubiquitin proteasome system (UBS) and autophagy, which also involves protein uibquitination. The UBS system is important in cell regulation and in response to damage and is implicated in neurodegenerative disease and aging. Having originally shown how this system drives the cell cycle and identified and purified the Anaphase Promoting Complex, we have actively engaged in understanding how that ubiquitin ligase and others control protein stability. The UBS is a vast system involving almost 1000 types of protein and the connections between substrates and regulators have been hard to identify. When identified these connections reveal new pathways of regulation. Very few targets of ubiquitin ligases have been identified; conversely, very few proteins that are known to be degraded in a regulated way have been mapped to the ligases that regulate their degradation. We have used single molecule measurements and cryoelectronmicroscopy to understand specificity in ubiquitination and degradation. Our next challenge is to understand the pathways of regulation
Q1. Is there a Protein Regulatory Network (PRN) in the sense that the term Gene Regulatory Network is used that connects the expression of one protein to the destruction of another and is this network densely connected with feedbacks and autoregulation?
Q2. How is specificity achieved in protein degradation?
Q3. How is protein degradation connected to cell growth, cell proliferation, neurodegeneration and aging?
To answer these questions we have been developed methods to find the ligases for any substrate, or the substrates for any ligases. This will lay the groundwork for detecting organization in the degradation side of regulatory biology. A special interest is the general instability of transcription factors, some of which are known to be strongly regulated by ubiquitin dependent degradation. We are also developing methods for identifying the “degradome” of a cell, which in some serious sense is the flip side of the transcriptome.