Probing life and death decisions with synthetic protein chemistry

Post-translational modifications (PTMs) of proteins control almost all biological processes, including cellular life and death decisions. Such processes serve to eliminate aberrant cells and are mediated by endogenous proteins - including the tumour suppressor p53 -, and can be hijacked by pathogen-encoded toxic proteins. Deciphering how PTMs regulate the activity of these “self-destruction” proteins is an important step in understanding the basic biology of controlled cell death and in providing a framework for the design of new antitumour proteins. However, mechanistic analysis of how PTMs effect structural and functional changes is hampered by the complexity of the underlying signalling pathways and thus requires chemistry-driven approaches which we develop. I will discuss our protein semisynthesis strategies to access “designer p53” and a viral anticancer protein bearing defined PTMs, and how were are deploying these proteins in functional assays in vitro and in living cells to gain new insights into how PTMs decide cell fate.   TBA