A strategy for modulation of enzymes in the ubiquitin system.

نویسندگان

  • Andreas Ernst
  • George Avvakumov
  • Jiefei Tong
  • Yihui Fan
  • Yanling Zhao
  • Philipp Alberts
  • Avinash Persaud
  • John R Walker
  • Ana-Mirela Neculai
  • Dante Neculai
  • Andrew Vorobyov
  • Pankaj Garg
  • Linda Beatty
  • Pak-Kei Chan
  • Yu-Chi Juang
  • Marie-Claude Landry
  • Christina Yeh
  • Elton Zeqiraj
  • Konstantina Karamboulas
  • Abdellah Allali-Hassani
  • Masoud Vedadi
  • Mike Tyers
  • Jason Moffat
  • Frank Sicheri
  • Laurence Pelletier
  • Daniel Durocher
  • Brian Raught
  • Daniela Rotin
  • Jianhua Yang
  • Michael F Moran
  • Sirano Dhe-Paganon
  • Sachdev S Sidhu
چکیده

The ubiquitin system regulates virtually all aspects of cellular function. We report a method to target the myriad enzymes that govern ubiquitination of protein substrates. We used massively diverse combinatorial libraries of ubiquitin variants to develop inhibitors of four deubiquitinases (DUBs) and analyzed the DUB-inhibitor complexes with crystallography. We extended the selection strategy to the ubiquitin conjugating (E2) and ubiquitin ligase (E3) enzymes and found that ubiquitin variants can also enhance enzyme activity. Last, we showed that ubiquitin variants can bind selectively to ubiquitin-binding domains. Ubiquitin variants exhibit selective function in cells and thus enable orthogonal modulation of specific enzymatic steps in the ubiquitin system.

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عنوان ژورنال:
  • Science

دوره 339 6119  شماره 

صفحات  -

تاریخ انتشار 2013