Kieft Lab research interests - overview
RNA is a remarkably versatile biological macromolecule, performing tasks ranging from encoding genetic information, performing catalysis, forming the scaffolds for large macromolecular machines, manipulating enzymes, binding small molecules, etc. It is safe to say that the RNA World is alive and well.
How does RNA perform so many biological tasks? The answer lies, in part, in the ability of RNA to form diverse three-dimensional structures whose complexity rivals that of proteins. Thus, to fully understand how RNA operates in healthy and diseased cells, we need to understand the structures of RNA in many ways: how structures form, their conformational dynamics, their stability, what they interact with, etc. But is not enough to just see structures, we need to use this structural information to understand the fundamental basis for RNA function and how it is dictated and regulated by structure.
The strategy of the RNA Kieft Lab has been to focus on exploring RNAs of viral origin. It is estimated that there are 1037 viral particles on Earth at any moment; these represent a rapidly evolving, structurally and functionally diverse treasure-trove of interesting and novel RNAs to explore. Because viruses are obligate cellular parasites, their RNAs are rapidly evolving new ways to interact with and manipulate the cellular biological machinery. Thus, by studying these RNAs we learn fundamental things about basic biological processes and how RNA operates in cells. What is found in viral RNAs is often later found to be true of cellular RNAs. Finally, viruses remain substantial human health threats and a detailed molecular understanding of how they manipulate their cellular hosts is required to develop new therapeutics.
Our goal is to understand these RNAs and their function in detail. We are not satisfied to know that that a certain mutation in a specific RNA causes a loss of function, we want to know why. We ask questions such as: What is the architecture and the conformational dynamics of a certain folded RNA? What does the RNA interact with and how? What are the implications of these interactions? Do mutations alter the structure of the RNA? How? What does this mean in terms of function? Our approaches include cell culture-based methods with disease relevant cells, in vitro activity assays, biochemical studies, x-ray crystallography, biophysical methods, and virology.
Current projects include: