Kylie J. Walters, Ph.D.
Structural Biophysics Laboratory
Bldg. 538/Room 167
Frederick, MD 21702
The Walters lab studies the structural and mechanistic basis of ubiquitin signaling events, proteasome function, and protein quality control. We use cell-based assays and a variety of biophysical techniques, our most powerful of which is NMR spectroscopy. This approach has helped to develop a mechanistic understanding of how the proteasome recognizes and processes its substrates. Working with other labs, we have identified Rpn1 and Rpn13 as substrate receptors in the proteasome that bind to ubiquitin chains and the shuttle factors that deliver ubiquitinated substrates to the proteasome. We have found that Rpn13 is targeted in its ubiquitin-binding domain by cell permeable molecules that restrict cancer cell proliferation. This work suggests that Rpn13 is a viable therapeutic target for human cancers. Small molecules that inhibit the catalytic core particle of the proteasome are approved for treatment of hematological cancers. Targeting of Rpn13 is expected to function synergistically with these approved molecules. We continue to study protein-protein interactions in the proteasome and other quality control pathways to understand the determinants of protein targeting for degradation as well as the mechanistic features that go awry in these pathways during carcinogenesis and neurological disorders.
Dr. Walters merges structural and cellular biology approaches to define the mechanisms of regulated protein degradation and quality control. Together with her collaborators and team members, she has made seminal scientific contributions that have defined how the proteasome recognizes its ubiquitinated substrates. These findings have led to new therapeutic strategies for cancer treatment. Dr. Walters’ training in the field of biophysics began as an undergraduate at Wesleyan University, where she used NMR to study the dynamic properties of DNA. She then obtained a Ph.D. in Biophysics from Harvard University, where she developed and used methods to study protein structure, dynamics, and interaction mechanisms. As an American Cancer Society Postdoctoral Fellow with Dr. Peter Howley in the Pathology Department at Harvard Medical School, she defined how a shuttle factor of the ubiquitin signaling pathway binds to the proteasome. In 2002, Dr. Walters joined the University of Minnesota as an Assistant Professor and was promoted to Associate Professor with tenure in 2008. During this time, her lab studied the mechanism by which ubiquitin signals for degradation by the proteasome. Dr. Walters was also awarded an American Cancer Society Research Scholarship from 2007-2011 for her work in protein quality control. In 2013, she moved to the Center for Cancer Research as a Senior Investigator, where she runs a vibrant research program that aims to apply basic science discoveries to translational benefit in the clinic. She currently serves on the CCR Science Board and as Acting Chief of the Structural Biophysics Laboratory.
Lu X, Nowicka U, Sridharan V, Liu F, Randles L, Hymel D, Dyba M, Tarasov SG, Tarasova NI, Zhao XZ, Hamazaki J, Murata S, Burke TR Jr, Walters KJ. Structure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets. Nat Commun. 2017;8:15540.
Randles L, Anchoori RK, Roden RB, Walters KJ. The Proteasome Ubiquitin Receptor hRpn13 and Its Interacting Deubiquitinating Enzyme Uch37 Are Required for Proper Cell Cycle Progression. J Biol Chem. 2016;291(16):8773-83.
Shi Y, Chen X, Elsasser S, Stocks BB, Tian G, Lee BH, Shi Y, Zhang N, de Poot SA, Tuebing F, Sun S, Vannoy J, Tarasov SG, Engen JR, Finley D, Walters KJ. Rpn1 provides adjacent receptor sites for substrate binding and deubiquitination by the proteasome. Science. 2016;351(6275).
He F, Wollscheid HP, Nowicka U, Biancospino M, Valentini E, Ehlinger A, Acconcia F, Magistrati E, Polo S, Walters KJ. Myosin VI Contains a Compact Structural Motif that Binds to Ubiquitin Chains. Cell Rep. 2016;14(11):2683-94.
Chen X, Lee BH, Finley D, Walters KJ. Structure of proteasome ubiquitin receptor hRpn13 and its activation by the scaffolding protein hRpn2. Mol Cell. 2010;38(3):404-15.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
This page was last updated on November 13th, 2019