My research interests are molecular recognition and protein-protein interactions as applied to ubiquitin biochemistry and ubiquitin-proteasome mediated protein degradation. The ubiquitin system is the major route of regulated intracellular proteolysis in all eukaryotes, and it is responsible for the control of numerous key regulatory proteins. In this pathway, proteins are modified by covalent attachment of ubiquitin, a 76-amino acid protein. Typically, multiple ubiquitins in the form of a polyubiquitin chain are elaborated from one or more lysine sidechains of the target protein. Classically, polyubiquitinated proteins are known to be recognized and degraded by the 26S proteasome, a 2.5 MDa ATP-dependent protease complex. However, depending upon the types of ubiquitin-ubiquitin linkages in the polyubiquitin chain, ubiquitination also can lead to other fates. Thus, mono- or polyubiquitin signals are used in endocytosis and protein trafficking, transcription activation, kinase activation cascades, and chromatin remodeling. Ubiquitin can be removed from conjugates through the action of various deubiquitinating enzymes (DUBs); consequently, many DUBs serve important regulatory functions.
Our research is focused on two areas of ubiquitin biochemistry: (1) assembly and recognition of linkage-specific polyubiquitin conjugates, and (2) the structures, mechanisms, and functions of deubiquitinating enzymes.
Projects funded in part by the TCNP of Lysine Modification include:
- K63-linked polyubiquitin synthesis in error-free DNA damage-tolerance pathway.
- Disassembly of K63-linked polyubiquitin by JAMM/MPN+ deubiquitinating enzymes.
- Structural basis for the K48-linkage specificity of the human deubiquitinating enzyme otubain 1.
- Basis for linkage-specific polyubiquitin binding by ubiquitin interacting motifs (UIMs).