Structure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets

Xiuxiu Lu, Urszula Nowicka, Vinidhra Sridharan, Fen Liu, Leah Randles, David Hymel, Marzena Dyba, Sergey G. Tarasov, Nadya I. Tarasova, Xue Zhi Zhao, Jun Hamazaki, Shigeo Murata, Terrence R. Burke, Jr. and Kylie J. Walters ()
Additional contact information
Xiuxiu Lu: Protein Processing Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute
Urszula Nowicka: Protein Processing Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute
Vinidhra Sridharan: Protein Processing Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute
Fen Liu: Protein Processing Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute
Leah Randles: Protein Processing Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute
David Hymel: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute
Marzena Dyba: Basic Science Program, Leidos Biomedical Research, Inc., Structural Biophysics Laboratory, Frederick National Lab
Sergey G. Tarasov: Biophysics Resource, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute
Nadya I. Tarasova: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute
Xue Zhi Zhao: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute
Jun Hamazaki: Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, University of Tokyo
Shigeo Murata: Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, University of Tokyo
Terrence R. Burke, Jr.: Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute
Kylie J. Walters: Protein Processing Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Proteasome–ubiquitin receptor hRpn13/Adrm1 binds and activates deubiquitinating enzyme Uch37/UCHL5 and is targeted by bis-benzylidine piperidone RA190, which restricts cancer growth in mice xenografts. Here, we solve the structure of hRpn13 with a segment of hRpn2 that serves as its proteasome docking site; a proline-rich C-terminal hRpn2 extension stretches across a narrow canyon of the ubiquitin-binding hRpn13 Pru domain blocking an RA190-binding surface. Biophysical analyses in combination with cell-based assays indicate that hRpn13 binds preferentially to hRpn2 and proteasomes over RA190. hRpn13 also exists outside of proteasomes where it may be RA190 sensitive. RA190 does not affect hRpn13 interaction with Uch37, but rather directly binds and inactivates Uch37. hRpn13 deletion from HCT116 cells abrogates RA190-induced accumulation of substrates at proteasomes. We propose that RA190 targets hRpn13 and Uch37 through parallel mechanisms and at proteasomes, RA190-inactivated Uch37 cannot disassemble hRpn13-bound ubiquitin chains.

Date: 2017
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DOI: 10.1038/ncomms15540

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