Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that regulates the activity, turnover, and trafficking of many proteins in cell signaling and adaptive stress responses. Hsp90 is also a remarkably dynamic molecular, with its conformational cycle coupled to its chaperone cycle. Using chemical cross-linking to covalently link residues in spatial proximity, we revealed the client-binding surface and Hsp90 induced conformational changes of a model client protein. In addition, we investigated cellular subpopulations of Hsp90 targeted by two Hsp90 inhibitors with distinct pharmacological efficacies and toxicological profiles. Our results suggest different conformational and posttranslational states of Hsp90 targeted by these inhibitors, and provide a potential biochemical mechanism for the formation of tumor promoting epichaperome. Assessment of various MS techniques in elucidating conformational changes will be discussed.

Speaker Link:
Faculty Host: Igor Kaltashov
Event Contact:
Laura Sedberry
lsedberry@chem.umass.edu
(413) 545-2585