Protein Disorder as a Mechanism of RNA Binding and Regulation

Project Abstract As factors involved in all aspects of RNA processing, RNA binding proteins (RPBs) are master regulators of gene expression. Despite this critical role, gaps remain in our understanding of how RBPs interact with RNA. Generally, RBPs have been considered to interact with typically single-stranded RNA via folded RNA-binding domains. However, many RBPs also have inherently disordered domains of low compositional complexity (low complexity domains, LCDs). In our current understanding of how RBPs interact with RNA, LCDs mediate protein- protein interactions and/or weak, non-specific RNA interactions. In contrast, a growing body of literature, and our own data, indicate LCDs are capable of specific binding to highly stable guanine-based helical RNA structures. These findings represent a reversal of the canonical binding mode: rather than folded protein binding to unstructured RNA, we have observed folded RNA binding to unstructured protein. My research program asks i) how do RBP LCDs interact with RNA? And, ii) what are the functional consequences of LCD-RNA interactions? This proposal outlines my research program to decipher basic mechanisms and dynamics of RBP-RNA interactions and define their role in normal and pathogenic pathways combining unbiased biochemical approaches with cell-based genomic strategies. Data generated from the proposed research will contribute broadly across all areas of cell biology by illuminating a more complete picture of RBP-RNA interactions.