Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 14, Pages E2011-E2018Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1601089113
Keywords
protein degradation; K48-polyubiquitination; E3 ligase; E2 enzyme; suramin
Categories
Funding
- Jiangsu Special Medical Expert Award
- NIH [1F30DK095572-01, GM61051/CA095634]
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada Fellowships
- Canadian Institutes of Health Research [MOP-14606]
- National Nature Science Foundation of China [81572710]
- Mount Sinai Technology and Development Fund Award
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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 small-molecule 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.
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