To carry out their functions in the healthy body, our cells use many thousands of types of proteins, each with a particular shape or "conformation". Proteins that have lost their correct shapes contribute to numerous disease, including cardiovascular diseases, neurodegenerative diseases (such as Parkinson's disease or ALS) and cancers. A specific group of proteins inside the cell work together to carry out "Protein quality control": they detect other proteins that have lost their conformation and either restore the correct conformations or get rid of these proteins (protein degradation). We use a powerful method termed "X-ray crystallography" to "see" the atomic structures of the quality-control proteins and to understand how they perform their crucial tasks inside the cell. The goals of our laboratory are to define how protein quality control is carried out, how it can fail or go awry in disease, and how we can use drugs and therapeutics to adjust protein quality control for disease treatment.
Our group broadly applies structural, biochemical and biophysical methods to investigate intracellular protein quality control (PQC). We are particularly interested in quality control of proteins that are intrinsically prone to aggregation or misfolding, as such proteins are disproportionaly involved in neurodegenerative diseases and diabetic cardiomyopathy. We are also interested in how protein quality control processes oppose transformation and tumorigenesis. The major current focus is CHIP, a ubiquitin ligase that is intimately associated with chaperone proteins and ubiquitinates many misfolding-prone proteins and marks them for destruction before they can aggregate. We study how CHIP interacts with the chaperone machinery, with its substrates, and with other proteins involved in ubiquitination. We are also studying how CHIP interacts with Bag2, a cochaperone that promotes protein refolding and inhibits premature or uncontrolled degradation of slow-folding proteins by CHIP. Finally, we are searching for compounds that can modulate CHIP, Bag2, and heat shock proteins. Such compounds may serve as starting points for drug design to actively control protein quality control in cancer, neurodegeneration and other pathological contexts.
Structural genomics and signaling domains. Hurley JH, Anderson DE, Beach B, Canagarajah B, Ho YS, Jones E, Miller G, Misra S, Pearson M, Saidi L, Suer S, Trievel R, Tsujishita Y PubMed:11796224 | 2002 | Trends Biochem Sci