Over 30 percent of the human genome encodes intrinsically disordered protein regions. These disordered regions can co-occur with neighboring folded domains or make up intrinsically disordered proteins alone. Despite being unstructured, intrinsically disordered regions are essential for cell survival and exert regulatory functions by encoding phosphorylation sites. However, the full impact of these regulatory mechanisms on cellular function is still largely unknown. This gap in knowledge is, in part, due to the dynamic nature of these disordered regions that make them difficult to study. Furthermore, dramatic conformational changes, as exemplified frequently by binding-induced protein folding, may also hinder studies seeking to understand the regulatory mechanisms associated with these post-translational modifications.
My lab seeks to understand the regulation of cellular processes through phosphorylation of intrinsically disordered regions of proteins. Because disordered regions regulated by phosphorylation are abundant in RNA-binding, my lab focuses on two excellent examples in histone mRNA stem-loop binding protein and Serine/Arginine rich splicing factors. Phosphorylation plays vital roles in both of these systems. The goal of our research is to understand how phosphorylation of disordered regions found in these proteins provides functional regulation of this class of proteins at the structural level. In addition, we also seek to determine how defects in phosphorylation of these regions result in cell death or carcinogenesis. Towards these goals, we use an array of biophysical approaches including Nuclear Magnetic Resonance, crystallography and small-angle x-ray scattering. This diverse array of techniques will allow us to characterize both the dynamic and structural aspects of disordered regions. These biophysical observations will then be assessed for their functional consequences using in vivo techniques. The culmination of our research efforts will result in a complete understanding (structural and functional) of how phosphorylation of intrinsically disordered regions of protein regulate cellular processes.
Keywords - Biochemistry, Regulation of Intrinsically Disordered Proteins, RNA-binding Protein Dynamics and Structure, NMR, Crystallography
