Posttranslational modifications (PTMs) are important events that lead to defined changes in protein function. Because these modifications occur after translation, they are difficult to understand based on the genetic template, and are often part of complex posttranslational networks. Our lab is focused on the innovation of chemical methods that can be used to understand the biology of two such PTMs: phosphorylation and ubiquitination. In the first case, we exploit the unique chemistry catalyzed by a family of bacterial effector proteins called phospholyases. These enzymes catalyze the irreversible elimination of phosphate on host proteins in order to subvert the host immune response. Our current work focuses on exploiting these proteins as a tool in studying the phosphoproteome. In the second case, we use existing chemical biology methods to develop a one-of-a-kind strategy that can track ubiquitin as it moves through its sequential, multi-enzyme cascade to become linked to a target protein in live cells. In both cases, the developed chemistry will be used to address longstanding questions about the role of these vital, yet elusive, PTMs in innate immunity, inflammation, autoimmune disease, and cancer.
Most chemistry that occurs within the cell is controlled by enzymes, yet there are several non-enzymatic PTMs that are observed to occur with selectivity in nature. Our lab is interested in understanding the molecular basis for non-enzymatic reactivity in biological systems. In particular, we aim to develop an understanding for how local environment on a protein surface can influence non-enzymatic reactivity and selectivity. In one project, we address this question through the study of glycation, a native non-enzymatic protein modification. Glycation is associated with many diseases, including cancer, diabetes, and other age-related disorders. However, it remains poorly understood. Our goal is to identify the features of local microenvironment that lead to glycation in a biological setting. This knowledge will enable the development of new tools that can be used to advance our understanding of glycation and its relationship to many diseases. In another project, we use engineered organocatalytic peptides to develop new chemistry that can report on changes in local environment, especially those involving transitions in tertiary structure. Together, this work will expand the range of non-enzymatic chemistry that can be harnessed to provide valuable chemical and synthetic biology tools.