Grant: Project Grant

All proteins must fold into a functional 3 dimensional structure in order to function in cells. However, extremely high protein concentrations in cells can lead to aggregation and loss of function before proper folding can occur. Molecular chaperones aid in the acquisition of the correct 3 dimensional structure by preventing inappropriate interactions between proteins that can lead to misfolding and aggregation. There are dozens of chaperone systems that each act in different ways to help proteins to fold. They can act as protective chambers, clamps, and even exert forces on vulnerable surfaces of the proteins they act on. The Hsp90 chaperone is critical for the folding of a large but specific set of substrate proteins that include important players in diseases like cystic fibrosis and cancer, and neurodegenerative diseases like Alzheimer's and Parkinson's disease. The mechanical basis for how Hsp90 acts on its substrates is not known but is linked to discrete physical states or 'poses' that the Hsp90 dimer can acquire. The complete set of poses that the Hsp90 dimer can assume collectively define the Hsp90 functional cycle. The rate at which Hsp90 progresses through all of the poses must be finely tuned in order to help individual substrate proteins to fold correctly. This tuning is carried out by a family of proteins called co-chaperones that are transiently recruited to Hsp90 under the influence of ATP and post-translational modifications. My lab is concerned in defining the relationship between the different poses of Hsp90 and specific co-chaperones and post-translational modifications. We employ a blend of biological (cell based), enzymatic, and structural assays to investigate the mechanics and biology of the Hsp90 system in yeast and mammalian systems.