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Tuesday, September 02, 2008
2:15 PM - 3:15 PM
CNLS Conference Room (TA-3, Bldg 1690)


q-Bio Seminar Series: Discovering the role of Protein Dynamics in RNA recognition motifs

Kathleen Hall
Washington University School of Medicine

RNA recognition motifs (RRMs) are a ubiquitous protein domain in eukaryotes that are present in nuclear and cytoplasmic proteins. There have been thousands of these domains identified by their sequence and predicted tertiary structure, and their very abundance leads to a fundamental question: how does a single RRM specifically bind to its target RNA and discriminate among all the other RNAs in the cell? We have studied the human U1A protein as a model system to answer this question, using NMR, thermodynamics, and molecular dynamics methods. The U1A protein is a component of the U1 snRNP, where it binds with sub-nanomolar affinity to stem-loop II of the U1 snRNA. We have developed a working model of the binding mechanism of U1A that is based on the dynamic motions present in the protein. In particular, the RNA binding surface of the domain must be pre-organized to respond to an incoming RNA. NMR relaxation data show that there are motions of the loops and tails of the protein that change in response to RNA binding, and molecular dynamics simulations of the protein and the RNA:protein complex show that those motions are correlated to create a productive binding surface. Disrupting the correlations with mutations in the protein also disrupt binding. This model will be tested with other RRMs, to determine if it is unique to U1A or generally true.

Host: Kevin Sanbonmatsu, T-10