Suramin inhibits cullin-RING E3 ubiquitin ligases Journal Article
| Authors: | Wu, K.; Chong, R. A.; Yu, Q.; Bai, J.; Spratt, D. E.; Ching, K.; Lee, C.; Miao, H.; Tappin, I.; Hurwitz, J.; Zheng, N.; Shaw, G. S.; Sun, Y.; Felsenfeld, D. P.; Sanchez, R.; Zheng, J. N.; Pan, Z. Q. |
| Article Title: | Suramin inhibits cullin-RING E3 ubiquitin ligases |
| Abstract: | Cullin-RING E3 ubiquitin ligases (CRL) control a myriad of biological processes by directing numerous protein substrates for proteasomal degradation. Key to CRL activity is the recruitment of the E2 ubiquitin-conjugating enzyme Cdc34 through electrostatic interactions between E3?s cullin conserved basic canyon and the acidic C terminus of the E2 enzyme. This report demonstrates that a smallmolecule compound, suramin, can inhibit CRL activity by disrupting its ability to recruit Cdc34. Suramin, an antitrypansomal drug that also possesses antitumor activity, was identified here through a fluorescence-based high-throughput screen as an inhibitor of ubiquitination. Suramin was shown to target cullin 1's conserved basic canyon and to block its binding to Cdc34. Suramin inhibits the activity of a variety of CRL complexes containing cullin 2, 3, and 4A. When introduced into cells, suramin induced accumulation of CRL substrates. These observations help develop a strategy of regulating ubiquitination by targeting an E2-E3 interface through small-molecule modulators. |
| Keywords: | protein degradation; suramin; e3 ligase; e2 enzyme; k48-polyubiquitination |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 113 |
| Issue: | 14 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2016-04-05 |
| Start Page: | E2011 |
| End Page: | E2018 |
| Language: | English |
| DOI: | 10.1073/pnas.1601089113 |
| PROVIDER: | scopus |
| PMCID: | PMC4833235 |
| PUBMED: | 27001857 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 May 2016 -- Source: Scopus |
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