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Strategies to crystalize the Hch1-Hsp90M complex

Natural Science

On-going

Discovery

Branching off Dr. Wolmarans Ph.D. work, students at King's looked into the structure of a protein called Hsp90 when in complex with one of its regulators, Hch1.

Hsp90 is a chaperone protein. This means it helps fold other proteins properly, protecting them from degradation. Many of these client proteins are necessary for tumour growth. Proteins such as such Hsp90 are essential for cancerous cell growth but less necessary for normal growth.

Hch1 is special because it stimulates the Hsp90 cycle as well as gives a resistance to Hsp90 inhibitors. Basically, when Hch1 isn’t present, Hsp90 is hypersensitive to drugs that slow down its cycle.

The structure of a protein (or complex, in this case) is closely connected with how it functions. For example, a screwdriver is designed to loosen and tighten screws but is terrible at removing a cork from a bottle. The form Hsp90 exists in when it’s bound to Hch1 allows it to be resistant to inhibitors but this complex has never been visualized before and the mechanism of Hch1 action isn’t well understood. Seeing what the complex looks like is essential to figuring out how Hch1 protects Hsp90 and by extension, how it makes cancer treatment less effective.

This research focuses on crystallization techniques used to help visualize Hch1-Hsp90M. It's a difficult process because it is necessary to “freeze” all the protein molecules in exactly the same orientation within a lattice. If this doesn't happen thee crystals either won’t form or can’t be visualized clearly. As such, most of the work thus far has involved trying to create ideal conditions for the protein to grow in so the protein can be isolated, purified, and modified for use in trials.

Where does this leave us? A more complete understanding of how Hsp90 associates with and is regulated by its co-chaperones will illuminate Hsp90’s role within many eukaryotes. Further study could include identifying how to utilize Hch1 in targeting Hsp90 inhibitors in cancerous cells.

Dr. Annerieke Wolmarans

Assistant Professor, Biology P: 780-465-3500 Ext. 8089
Education
  • B.Sc., University of Alberta, 2011
  • Phd., University of Alberta, 2017

Jordan Scheuermann (B.Sc. '19)