Although man is encoded in just 20,000 genes, post-transcriptional and translational modifications ensure that these genes are fully leveraged to generate the entire complexity of human life. Post-translational modifications (PTMs), in particular, enable the diversification of gene products through chemical functionalization of the canonical proteinogenic amino acids. These modifications expand the functional and structural repertoire of amino acid residues incorporated into proteins in order to endow enzymes with essential biochemical functions, regulate signaling pathways or protein-protein interactions, control enzymatic activity and stability, direct subcellular localization, and mediate the flow of information from one biological entity to another. Through phosphorylation, farnesylation, ubiquitylation, and so forth, tens of thousands of genes give rise to millions of protein isoforms present within our cells at any given time. The ability to dynamically toggle between the myriad isoforms allows cells to regulate biological processes on a much finer time scale than is possible through changes in gene expression, allowing them to respond rapidly to internal and external stimuli. Being able to introduce PTMs, especially those with new and expanded functionalities, on specific proteins in a highly controlled manner is both impactful and transformative. In this application, we propose a method for manipulating protein function through chemically-controlled post-translational modification of protein surfaces.
Disease often results from the improper or dysregulated interaction between two or more proteins. We seek to develop a new technology that will enable us to uncover important protein-protein interactions that occur in the cell but are too transient to be seen using currently available methods. Ultimately, the proposed research will have a broad impact on our ability to discover novel protein targets for the development of new therapeutic agents.
