Kylie J. Walters, Principal Investigator

Using Nuclear Magnetic Resonance Spectroscopy to Reveal Protein Structures and Protein-Protein Interactions

This research group is using nuclear magnetic resonance (NMR) spectroscopy to reveal protein structures and protein-protein interactions. Projects in the lab focus on proteins associated with human cancers, with the aim of using structural knowledge to design molecular inhibitors against specific oncoproteins. One major topic of the lab is the study of proteins associated with acute myeloid leukemia (AML). AML is associated with fusion proteins, produced as a result of chromosome translocations. Often the fusion proteins involve dimerization domains of one protein fused to a protein tyrosine kinase. Such tyrosine kinase dimers are constitutively active and misfunction to cause cancer. The group is using their structural knowledge of the dimerization domain of a fusion protein associated with AML to design a molecular inhibitor that blocks dimerization.

Additionally, this group is studying the mechanisms that have evolved in mammals for deoxyribonucleic acid (DNA) repair. Nucleotide excision repair (NER) and base excision repair (BER) remove damaged DNA that could otherwise cause cell death, tissue degeneration, aging, and cancer. The hHR23 proteins are required for recognition of damaged DNA and stimulation of NER, which they mediate by interacting with the XPC (xeroderma pigmentosum group C) protein. With a similar function in BER, the importance of these proteins is further evidenced by the embryonic lethality in mice that results from their deletion. The hHR23 proteins also play a role in proteasome-mediated degradation, suggesting that they serve as a link between regulated protein degradation and DNA repair, two processes crucial for proper cellular function. The group is solving the solution structure of the 40 kDa hHR23 protein. Furthermore, by using NMR spectroscopy, they are elucidating the proteasomebinding surface of hHR23. Using this knowledge, the group intends to design mutant versions of hHR23 that no longer bind the proteasome to be used in in vivo assays to ascertain the relevance of the hHR23-proteasome interaction in NER.

Research Group

Patrycja Lech, Staff
Qinghua Wang, Graduate Student Researcher