RT Journal Article
SR Electronic
T1 A Strategy for Modulation of Enzymes in the Ubiquitin System
JF Science
JO Science
FD American Association for the Advancement of Science
SP 590
OP 595
DO 10.1126/science.1230161
VO 339
IS 6119
A1 Ernst, Andreas
A1 Avvakumov, George
A1 Tong, Jiefei
A1 Fan, Yihui
A1 Zhao, Yanling
A1 Alberts, Philipp
A1 Persaud, Avinash
A1 Walker, John R.
A1 Neculai, Ana-Mirela
A1 Neculai, Dante
A1 Vorobyov, Andrew
A1 Garg, Pankaj
A1 Beatty, Linda
A1 Chan, Pak-Kei
A1 Juang, Yu-Chi
A1 Landry, Marie-Claude
A1 Yeh, Christina
A1 Zeqiraj, Elton
A1 Karamboulas, Konstantina
A1 Allali-Hassani, Abdellah
A1 Vedadi, Masoud
A1 Tyers, Mike
A1 Moffat, Jason
A1 Sicheri, Frank
A1 Pelletier, Laurence
A1 Durocher, Daniel
A1 Raught, Brian
A1 Rotin, Daniela
A1 Yang, Jianhua
A1 Moran, Michael F.
A1 Dhe-Paganon, Sirano
A1 Sidhu, Sachdev S.
YR 2013
UL http://science.sciencemag.org/content/339/6119/590.abstract
AB 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.