Kylie J. Walters, Ph.D.
A primary research emphasis of the Walters lab is to define the mechanistic determinants of regulated protein degradation by the proteasome and of protein quality control pathways. Dysfunction of these processes is associated with disease, and specific inhibitors of machinery critical to protein clearance are used as anti-cancer therapeutics. The Walters lab comprises a vibrant assembly of researchers with diverse expertise, enabling the seamless merger of structural and cell biology techniques. The group has made key discoveries that have helped define how the proteasome recognizes its substrates and established a new approach to target the ubiquitin-proteasome pathway that has clinical promise.
1) structural biology, 2) biophysics, 3) ubiquitin signaling, 4) proteasome, 5) NMR spectroscopy
Contact Info
Center for Cancer Research
National Cancer Institute
Bldg. 538/Room 167
Frederick, MD 21702
Ph: 301-228-4374
kylie.walters@nih.gov
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.
Selected Key Publications
- Science. 351: pii: aad9421, 2016. [ Journal Article ]
- Nat. Commun. 11: 1291, 2020. [ Journal Article ]
- Structure. 28: https://doi.org/10.1016/j.str.2020.02.007, 2020. [ Journal Article ]
- Nat. Commun. 8: 15540, 2017. [ Journal Article ]
- Cell Rep. 14(11): 2683-94, 2016. [ Journal Article ]
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.
| Name | Position |
|---|---|
| Anthony Cruz | Postbaccalaureate Fellow (CRTA) |
| Gwen Buel Ph.D. | Postdoctoral Fellow (CRTA) |
| Xiang Chen, Ph.D. | Staff Scientist |
| Anne Kaplan Ph.D. | Postdoctoral Fellow (CRTA) |
| Olumide Kayode Ph.D. | Postdoctoral Fellow (CRTA) |
| Xiuxiu Lu Ph.D. | Research Fellow (Visiting) |
| Vasty Osei Amponsa Ph.D. | Postdoctoral Fellow (Visiting) |
| Brandon J. Wright Ph.D. | Postdoctoral Fellow (CRTA) |
Current position: Scientist at Celgene Corporation
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Current position: Undergraduate Student at Florida State University
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Current position: NMR Facility Manager, St. Louis University
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Current position: Scientific Advisor, Center of New Technologies, University of Warsaw
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Current position: Undergraduate student at Lebanon Valley College
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Current Position: Principle Scientific Consultant, 100BioTech, Co. Ltd.
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Current position: Chemist, Syntiron
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Current position: Student at University of Virginia
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Current position: Undergraduate student at University of Maryland, College Park
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Current position: Faculty at Shanghai Institute of Materia Medica
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Current position: Postdoctoral Fellow at Vanderbilt University
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Current position: Undergraduate student at the University of Minnesota
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Current position: Senior Immunogenetic Specialist at Be The Match operated by National Marrow Donor Program
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Current position: Assistant Clinical Professor at University of New England, Maine
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Current position: Faculty at Shanghai Institute of Materia Medica
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Current position: Visiting Assistant Chemistry Professor, St Olaf College
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Current position: Research Scientist, R&D Systems Inc.
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Current position: Instructor, University of Delaware
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Current position: Professor at St Cloud State University Department of Chemistry
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March 10th 2020: Congratulations to Gwen Buel and Xiang Chen on their discovery of a binding site for E6AP at the proteasome, published today in Nature Communications.
May 5th 2020: Congratulations to Xiuxiu Lu and Danielle Ebelle on revealing the mechanism of how hRpn13 binds K48 ubiquitin chains, published today in Structure, with an excellent commentary by Jeroen Roelofs.
Members of the group celebrate achievements of 2019 at a restaurant in downtown Frederick.
Congratulations to Dr. Xiuxiu Lu for receiving a Best Poster Award at the 2018 NCI Structural Biology Retreat
Congratulations to Dr. Xiang Chen and Dr. Kylie Walters for receiving CCR Federal Technology Transfer Awards
Congratulations to Dr. Gwen Buel for being selected as a winner of NIH Fellows Award for Research Excellence (FARE) 2019 competition.
Congratulations to Dr. Xiang Chen for being selected as a winner of NIH Fellows Award for Research Excellence (FARE) 2017 competition. Xiang used this award to attend and present a poster at Cold Spring Harbor Laboratory Conference “The ubiquitin Family” on April 18-22, 2017.
Congratulations to Dr. Xiuxiu Lu for being selected to give an oral presentation at the ASBMB 2017 meeting in Chicago on April 22-26.
Dr. Vinidhra Sridharan presented a poster at the Cold Spring Harbor Laboratory Conference “The Ubiquitin Family”, April 18-22, 2017.
The Protein Processing Section pose for a photo during the summer of 2018
