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Dr. Kylie Walters

Acting Chief: Structural Biophysics Laboratory

National Institutes of Health / National Cancer Institute


November 30th, 2018 – Fall Seminar

Time and Location: Noon in Meyerhoff Chemistry, Room 120

Host: Dr. Mike Summers

Substrate recognition and small molecule targeting of the proteasome”


Regulated protein degradation in eukaryotes is performed by the proteasome, which contains a 20S catalytic core particle (CP) capped at either end by a 19S regulatory particle (RP). Proteasome activity is dysregulated in myriad diseases, and specific inhibitors of the CP used to treat hematological cancers. Substrates for the proteasome are typically marked by post-translational addition of ubiquitin chain(s). The proteasome captures such substrates through receptors located in the RP that bind directly to ubiquitin, or to shuttle factors that bind the proteasome with ubiquitin-like domains and ubiquitin with ubiquitin-associated domains. Together with our collaborators, we have found that the RP houses three major receptors for ubiquitinated substrates, Rpn1, Rpn10 and Rpn13. We have used NMR spectroscopy to define how Rpn13 is assembled into the proteasome and to reveal how each receptor binds to ubiquitinated substrates. In our newest discovered substrate receptor Rpn1, tandem recognition sites for the ubiquitin fold exist within a toroid structure that provides at one location an interaction surface for ubiquitin or the shuttle factor Rad23 and at the other, a binding site for the UBL domain of deubiquitinating enzyme Ubp6/Usp14. We have determined the structure of the Rpn1 ubiquitin recognition site with K48-linked ubiquitin chains or with the Rad23 UBL domain. Collectively, our studies provide mechanistic understanding of how the proteasome captures its ubiquitinated substrates and paves the way for new strategies to target protein degradation.