Structural Basis for the Inhibitory Effects of Ubistatins in the Ubiquitin-Proteasome Pathway

Mark A. Nakasone, Timothy A. Lewis, Olivier Walker, Anita Thakur, Wissam Mansour, Carlos A. Castañeda, Jennifer L. Goeckeler-Fried, Frank Parlati, Tsui Fen Chou, Ortal Hayat, Daoning Zhang, Christina M. Camara, Steven M. Bonn, Urszula K. Nowicka, Susan Krueger, Michael H. Glickman, Jeffrey L. Brodsky, Raymond J. Deshaies, David Fushman

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

The discovery of ubistatins, small molecules that impair proteasomal degradation of proteins by directly binding to polyubiquitin, makes ubiquitin itself a potential therapeutic target. Although ubistatins have the potential for drug development and clinical applications, the lack of structural details of ubiquitin-ubistatin interactions has impeded their development. Here, we characterized a panel of new ubistatin derivatives using functional and binding assays. The structures of ubiquitin complexes with ubistatin B and hemi-ubistatin revealed direct interactions with ubiquitin's hydrophobic surface patch and the basic/polar residues surrounding it. Ubistatin B binds ubiquitin and diubiquitin tighter than a high-affinity ubiquitin receptor and shows strong preference for K48 linkages over K11 and K63. Furthermore, ubistatin B shields ubiquitin conjugates from disassembly by a range of deubiquitinases and by the 26S proteasome. Finally, ubistatin B penetrates cancer cells and alters the cellular ubiquitin landscape. These findings highlight versatile properties of ubistatins and have implications for their future development and use in targeting ubiquitin-signaling pathways. Nakasone et al. characterize a panel of ubistatin derivatives and show that ubistatins inhibit ubiquitination and shield ubiquitin conjugates from disassembly by a range of deubiquitinases and by the 26S proteasome. Ubistatin B penetrates cancer cells and alters the cellular ubiquitin landscape. The structures of ubiquitin complexes with ubistatin B and hemi-ubistatin revealed that hydrophobic and charge/polar interactions are critical for ubistatin:ubiquitin binding.

Original languageEnglish (US)
Pages (from-to)1839-1855.e11
JournalStructure
Volume25
Issue number12
DOIs
StatePublished - Dec 5 2017

Keywords

  • NMR
  • SANS
  • deubiquitination
  • polyubiquitin
  • ubiquitin-proteasome system
  • ubiquitination
  • ubistatin

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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  • Cite this

    Nakasone, M. A., Lewis, T. A., Walker, O., Thakur, A., Mansour, W., Castañeda, C. A., Goeckeler-Fried, J. L., Parlati, F., Chou, T. F., Hayat, O., Zhang, D., Camara, C. M., Bonn, S. M., Nowicka, U. K., Krueger, S., Glickman, M. H., Brodsky, J. L., Deshaies, R. J., & Fushman, D. (2017). Structural Basis for the Inhibitory Effects of Ubistatins in the Ubiquitin-Proteasome Pathway. Structure, 25(12), 1839-1855.e11. https://doi.org/10.1016/j.str.2017.10.007