Recognition, activation and targeted degradation of protein kinases clients by the HSP90-molecular chaperone

The normal functioning of cells is controlled by nano-molecular machines made up of protein molecules. Many of these require help from specialised nano-machines called chaperones, which look after component proteins until they are needed. Many of the mutated or overabundant protein molecules that turn a well-behaved cell into an uncontrolled cancer, are particularly dependent on chaperones. Drugs that stop chaperones working cause these aberrant proteins to be destroyed, thereby selectively killing cancer cells.

Kinases are proteins that are often aberrant in cancer and they depend on a chaperone called HSP90. We wish to understand how these cancer-associated kinase proteins gain access to HSP90 in the cell, how HSP90 binds to them and stabilises them, how they are eventually released from HSP90, and how they become destroyed when HSP90 is stopped from working by specific drug molecules.

Our findings will shed light on the process of cancer development and the way drugs that target chaperone molecules can be used in cancer treatments.