- Research overview
One of the main challenges remaining in biology is to understand how an organism's, or individual cell's, particular genetic code, or genotype, is relayed into its physical characteristics, or phenotype. The inability to predict phenotype from a known genotype often lies in the fact that numerous mechanisms of control act in concert, or opposition, to modulate the production and behavior of a single protein. Systems biology has emerged in an attempt to explore the concept that the cell is comprised of self-organizing, dynamic networks of proteins and genes, rather than individual components working in relative isolation in the cell. These networks would provide an adaptive response to varying conditions often imposed by the environment or the genetics of the organism itself. The dynamic nature of these networks would also allow the cell, or organism, to compensate for the stress of missing or misfunctional components, possibly by either reorganizing a single network or distributing the stress among many networks. This interplay between networks, or within a single network, is what often confounds the prediction of phenotype from genotype. It's the dynamic interactions within, and between, such networks that broadly interests us. And with the recent explosion of high-throughput genomic and proteomic techniques, the promise of solving the details of these networks has reached a new attainable level.
Within the cellular bag of tricks, protein modification is one way that protein function can be altered rapidly, either reversibly or irreversibly. Protein modification can also change the way in which the DNA code is read, copied, or packaged. Thus, it is likely that protein modification is a root mechanism at the heart of the dynamic, adaptive behavior of networks. As such, understanding the pattern of protein modifications in response to internal and external chemical concentrations is the key to understanding the dynamism within a network. There are numerous molecules that serve as modifiers of proteins, ranging from small molecule moieties like acetyl, methyl and phosphate groups to small proteins like ubiquitin, SUMO and RUB. Many of these modifications work in conjunction with each other to effect some change in function for their target protein. Many of these modifications can also work in opposition to each other to counteract different possible functionalities for a particular target protein. We are most interested in the class of modifiers that are themselves proteins, for it is an intriguing facet of biology that one protein is used to modify the behavior of another, although such a moiety most likely brings an added level of complexity that cannot be achieved by small molecule adapters. Out of this class, ubiquitin is one of the most fascinating because it is employed by the cell with such dramatic depth and breadth that it would appear no cellular process is left untouched by modification with ubiquitin. Our studies in elucidating various roles in which ubiquitin is employed are described below in more detail.
- The other projects
There are a variety of projects going on in the lab from devising global ubiquitin proteomic strategies that will allow us to elucidate the functions of ubiquitin-protein ligases and ubiquitin proteases, to understanding the roles ubiquitination and deubiquitination play in gene transcription and silencing, to uncovering the ways in which the cell destroys aberrant proteins in the nucleus for the purposes of protein quality control. Move mouse over pictures to learn more...