This action funds an NSF Postdoctoral Research Fellowship for FY 2009 using funds from the American Recovery and Reinvestment Act of 2009 (Public Law 111-5). The training and development plan is entitled "How ubiquitin protein chains elicit different cellular signals" for Carlos Castaneda. The host institution for this research is the University of Maryland, College Park, and the sponsoring scientist is David Fushman.
Large proteins are commonly comprised of domains, which are protein "modules" that can exist independently with their own structure and function. The combination and arrangement of these domains are responsible for the diversity of protein function. Polyubiquitin is an example of such a protein that is composed of a chain of ubiquitin proteins linked together at distinct sites. Polyubiquitin chains of different linkages signal for different events in the cell, including protein degradation, DNA repair and cell cycle control. Little is known about how these chains evoke different signals in the cell. This project entails making modifications to the linkage and interface between ubiquitin proteins and then observing how these changes affect the overall structure and dynamics of polyubiquitin chains. Site-directed mutagenesis is employed to alter both the length of the linker region and the "stickiness" of the interface between ubiquitin proteins. Both experimental and computational techniques are used to study these chains in solution structurally and dynamically at atomic resolution and to model how these chains respond to changes in conditions, such as pH.
This study contributes to addressing a difficult question in biophysics: how do protein structure and dynamics govern biological function? This question impacts many areas of basic science research, including protein engineering, molecular modeling and biological informatics. Training goals include learning protein dynamics measurements and protein structure determination using nuclear magnetic resonance, and developing computational skills in molecular modeling, molecular dynamics simulations and structure-based calculations. This research is tightly integrated with the mentoring of undergraduate and graduate students in molecular biophysics and biochemistry.
