The International Research Fellowship Program enables U.S. scientists and engineers to conduct nine to twenty-four months of research abroad. The program's awards provide opportunities for joint research, and the use of unique or complementary facilities, expertise and experimental conditions abroad.
This award will support a twenty-four-month research fellowship by Dr. Elizabeth Valentine to work with Dr. Maria R. Conte at Kings College London in the United Kingdom.
The objective of this proposal is to study the structure/function relationship of human La protein and its RNA substrates. The processing and maturation of RNA molecules in the nucleus are crucial to the survival of all organisms. La protein is a ubiquitous, highly abundant phosphoprotein that binds to most, if not all, nascent Polymerase III RNA transcripts and aids in the folding and maturation of these RNA molecules. La is a modular protein consisting of three distinct domains and a relatively unstructured C-terminal tail. While there are three dimensional structural data of the three isolated domains of La and one very recent RNA-bound structure of the first two domains of La in tandem, little is known about how the other domains in La interact with each other and how La interacts with such a diverse array of RNA molecules. Additionally, little is know about how these interactions modulate La function, La protein-protein interactions and La-RNA interactions. The technical approach of this project will involve a variety of biochemical, biophysical and structural methods; in particular NMR spectroscopy will be used to study the structure-function relationship of La and bound RNA molecules. The expected result of these experiments is the determination of the structural and specificity requirements for La binding to various RNA molecules, including both normal physiological RNA targets and viral RNA targets. The questions of how La interacts with various RNA molecules with seemingly different properties and how the specificity of La interactions is determined will be answered. These studies will lead to a deeper understanding of the role of La in both normal and disease states in humans. Maria Conte's laboratory published the first structures of human La protein and has extensive expertise in the study of RNA-protein interactions by NMR spectroscopy. The plan is to combine the studies of protein structure and dynamics using NMR spectroscopy with more biochemical approaches in order to elucidate the structure-function relationship of biologically important protein systems. This project will advance the field of RNA biology by elucidating RNA-binding interactions of a key protein involved in RNA maturation and folding. Furthermore, this project will provide information on how proteins recognize and bind to specific RNA molecules and how specificity is established.
