Research

Regulation of the Hsp90 ATPase cycle

The heat shock protein 90 (Hsp90) is a molecular chaperone that is responsible for the folding, conformational maturation, activation, and assembly of hundreds (and possibly thousands) of substrates called 'clients'. These clients include transcription factors, kinases, membrane proteins, and many other proteins with no obvious structural similarity. Hsp90 is a dimer of two identical subunits each comprised of an N terminal ATPase domain, a middle domain, and a C terminal domain that serves as the primary dimerization interface. ATP hydrolysis by Hsp90 requires numerous conformational changes after ATP docking in the active site. The N domains dock with the middle domains, a lid domain closes over ATP, the N domains come together, and beta strands are exchanged between the two N domains. There are considerable questions surrounding the order in which these events take place, as well as how they are regulated by co-chaperone proteins and post-translational modifications. 

We employ yeast and mammalian cell-based models to interrogate the Hsp90 system as well as structural and biochemical approaches to understand the mechanics of the Hsp90 client activation cycle.

Proteostasis and Tumour Immunogenicity

The adaptive immune system can target and destroy cancer cells through the recognition of neoantigenic peptides in type I major histocompatibility complexes. The mutational burden of any cancer cell confers vulnerability to the immune system because of the many proteins with altered sequences that are encoded in the cancer cell genome. Chaperones like Hsp90 play a critical role in maintaining the balance between the folding of these often thermodynamically compromised substrates and their degradation. We explore the relationships between cellular quality control pathways and tumour cell immunogenicity.

Proteome Turnover Analysis

All molecular chaperone systems participate in the maintenance of proteostasis. Determining the clientele of Hsp90 and its co-chaperones is made difficult by the transient nature of chaperone/client complexes. We are exploring global proteome profiling techniques to better understand how perturbations in the Hsp90 system change the turnover rates of proteins under different conditions.