My lab is trying to understand how the cell achieves accurate control of protein degradation and how its failure may lead to neurodegeneration and aging.

One half percent of protein in our body is synthesized daily, while the same is catabolized to maintain homeostasis. Effective protein degradation thus must be carried out with no less efficiency and precision (specificity) than transcription and translation. Central in a large number of biological functions is the ubiquitin-proteasome system responsible for the spatial and temporal control of protein stability. As many cellular processes are regulated by transcription/translation, tuning the rates of protein degradation has been shown to be involved in regulating cell cycle progression and differentiation. To meet the specificity requirement for protein degradation, ubiquitylation pathways generate a large number of ubiquitin configurations on substrate proteins; this has been called the “ubiquitin code” which must be read by the proteasome and converted into a rate of degradation.

We evolve modern enzymological methodology, namely single-molecule fluorescence/force spectroscopy, cryo-electron microscopy and molecular dynamics simulation, to investigate how the information in ubiquitin configurations is decoded by the proteasome, a universal molecular machine in eukaryotic species, to command accurate degradation of cellular proteins. We also develop systems and high-throughput approaches to investigate the state of protein degradation on a genome-wide scale and how misregulation of the degradation machinery skews the degradome, underlying various disorders.