Investigation of sequence and structural characteristics of interfaces in RNA-protein complexes

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2023-05
Authors
Lewis, Beatrice Ada
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Dobbs, Drena
Miller, W. Allen
Henderson, Eric R
Jernigan, Robert L
Lawrence-Dill, Carolyn J
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Genetics, Development and Cell Biology
Abstract
RNA-protein interactions are an essential component of many cellular processes, with roles ranging from the well-studied, such as mRNA synthesis, transport, processing, and translation, to the more recently identified, such as transcriptional regulation by small RNAs and chromatin remodeling by long non-coding RNAs. The goal of this dissertation is to elucidate the common principles underlying RNA-protein recognition in its many roles, through analysis of both sequence and structural properties of proteins and RNAs involved in intermolecular complexes. First, we introduce the Protein-RNA Interface Database (PRIDB), a comprehensive database of experimentally elucidated RNA-protein complexes. We describe the data sources integrated to provide the data contained in the database, the types of analyses for which the database can be used, and methods for accessing the data. Second, using PRIDB, we analyze the sequences and structures of known RNA-protein complexes. In the sequence analyses, we examine patterns in the distribution of binding residues across the primary sequence of RNA-binding proteins, and find that these residues tend to be clustered. In the structural analyses, we first examine the degree of interconnectedness between residues involved in protein-RNA interfaces and demonstrate that these interfaces are densely interconnected, with the majority of interfacial residues involved in interaction with multiple partner residues. We then examine the frequency with which residues participate in specific atomic contacts, relative to the background frequency of those contacts. We find that certain overrepresented pairs are critical to the interfaces in which they appear, forming the basis of biologically significant modes of interaction. Finally, we exploit the motifs generated in our sequence and structure analyses to develop a novel method for predicting the interfacial residues in both the RNA and the protein components of protein-RNA complexes. Taken together, these studies provide a valuable new database and new software tools for interrogating and predicting RNA-protein interactions. They identify distinctive structural features of RNA-protein interfaces and a new set of interfacial motifs that can be used not only to predict interfacial residues in complexes, but also to predict binding partners in RNA-protein complexes.
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