RNA binding domains (RBDs;also known as RNA recognition motifs) are the most common RNA binding structural element in eukaryotes and are present in 0.5-1% of human genes. Given the abundance of these structures and their role in such important and diverse cellular processes as splicing regulation, translation, nuclear transport, and cytoplasmic trafficking of RNA, it is inconceivable that these domains play no role in human disease. Indeed, proteomics studies and systems biological approaches have implicated RNA binding proteins in multiple cancers and paraneoplastic disorders, neurological disorders, and disorders of muscular atrophies. Reaching an understanding of the RNA binding mechanisms of this group of proteins is therefore important. But although the RNA binding mechanisms of a few RBDs have been characterized, the RNA-protein interactions are incredibly diverse. This is in spite of the nearly identical structure of the RBDs themselves. To the end of understanding the RNA binding m,echanism of RBDs in general, we intend to study RNA binding of SNF, a chimeric protein in Drosophila that is highly homologous to both U1A and U2B"""""""", proteins found in small nuclearribonucleoproteinparticles (snRNPs) and thus implicated in pre-mRNA splicing. SNF is unique in that it functions in place of both proteins;unlike U1A and U2B"""""""", SNF binds both both U1 snRNA and U2 snRNA in vivo and in vitro. We will investigate the mechanisms by which SNF recognizes and interacts with its distinct RNA binding partners using biochemical and biophysical methods, including NMR and mutant analysis. Furthermore, it appears that some protein-protein interactions modulate SNF's interaction with its RNA binding partners. U2A'and SXL (Sex-lethal) are known to interact with SNF. We will investigate how these interactions affect SNF and its ability to bind its target RNAs using biochemical and biophysical methods, including NMR and mutant analysis. RNA-protein interactions underlie many essential biological processes, including RNA splicing, translation, and RNA transport. It is therefore not surprising that dirsuptions of these interactions are implicated in such diverse disease processes as cancers, neurological disorders, and muscular atrophies. Understanding the nature of RNA-protein interactions should allow us to better understand how changes in these interactions contribute to disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-CB-N (29))
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Gaillard, Shawn R
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Washington University
Schools of Medicine
Saint Louis
United States
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Williams, Sandra G; Hall, Kathleen B (2014) Binding affinity and cooperativity control U2B?/snRNA/U2A' RNP formation. Biochemistry 53:3727-37
Williams, Sandra G; Hall, Kathleen B (2014) Linkage and allostery in snRNP protein/RNA complexes. Biochemistry 53:3529-39
Delaney, Kimberly J; Williams, Sandra G; Lawler, Mariah et al. (2014) Climbing the vertebrate branch of U1A/U2B? protein evolution. RNA 20:1035-45
Williams, Sandra G; Harms, Michael J; Hall, Kathleen B (2013) Resurrection of an Urbilaterian U1A/U2Býýý/SNF protein. J Mol Biol 425:3846-62
Williams, Sandra G; Hall, Kathleen B (2011) Human U2B? protein binding to snRNA stemloops. Biophys Chem 159:82-9
Williams, Sandra G; Hall, Kathleen B (2010) Coevolution of Drosophila snf protein and its snRNA targets. Biochemistry 49:4571-82