Molecular basis for the recognition of N- and C-degrons

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Each cell in our body contains thousands of proteins, and the protein homeostasis need to be precisely controlled in order to maintain a balanced and functional proteome. The abundance of proteins in cells is determined by the rates of protein synthesis and degradation. Any unwanted proteins need to be degraded rapidly. In addition, misfolded, aggregated and abnormal proteins need to be degraded in a timely fashion as well. The ubiquitin-proteasome system (UPS) is a critical protein degradation pathway that maintains protein homeostasis, and aberrations of the UPS associated proteins contribute to various human diseases, including neurodegeneration, abnormal aging and cancers. In the ubiquitin-proteasome system, proteins targeted for degradation are ubiquitinated by a cascade of enzymes: ubiquitin-activating (E1), ubiquitin-conjugating (E2) and ubiquitin-ligase (E3) enzymes, and the ubiquitinated substrates are subsequently degraded into short peptides by the 26S proteasome. An E3 ubiquitin ligase specifically targets its substrates by recognition of degradation signals present in substrates, such as signal motifs located  at the N-termini or C-termini of the target proteins. Virtually all proteins have their unique N- or C-terminal sequence contexts, which can become degradation signals and be recognized by respective E3 ligases for degradation through distinct N- or C-degron pathways. A comprehensive understanding of how the recognition of specific degrons by E3 ubiquitin ligases drives selective protein degradation is critical if we are to attain a deeper understanding of the ubiquitin-proteasome system. In this discovery research program, we aim to characterize these degradation pathways systematically through investigating their substrate recognition mechanisms, identification of physiological substrates for each pathway and develop specific small-molecule inhibitors or chemical probes for these systems. Specifically, we would like to focus on the following three aims: 1) Understand substrate sequence selectivity and catalytic mechanism of protein arginylation by ATE1 in the Arg/N-degron pathway; 2) Delineate the Arg/C-degron sequence selectivity and recognition mechanism by FEM1C in the Arg/C-degron pathway; and 3) Determine why FEM1B has different C-terminal sequence selectivity than FEM1C, which will shed lights on the labor of division among the different FEM1 members in the Arg/C-degron pathway. This research program will not only be valuable to better elucidate the roles of degron pathways in fundamental biological processes, but also contribute to the advent of therapeutic agents against human diseases associated with these degron pathways, ultimately improving the health of Canadians and people around the world. Last but not the least, this research program will provide a solid  platform to train future basic and application scientists in the fields of protein science and ubiquitin biology.