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Contributions made to the proteasome by substrate receptors

   
Air date: Tuesday, October 29, 2019, 11:00:00 AM
Time displayed is Eastern Time, Washington DC Local
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Description: Biowulf 20th Anniversary Seminar Series

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 UBL domains and ubiquitin with UBA 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. We also find that targeting the proteasome through Rpn13 with chalcone derivatives leads to accumulation of ubiquitinated proteins, apoptosis, and restricted tumor growth in mouse xenograft models. This talk reports a new functional role for a substrate receptor at the proteasome.

For more information go to https://hpc.nih.gov/training/
Author: Kylie Walters, Ph.D., NCI, NIH
Runtime: 1 hour