Chapter

Conjugation and Deconjugation of Ubiquitin Family Modifiers

Volume 54 of the series Subcellular Biochemistry pp 41-56

Control of Cullin-Ring Ubiquitin Ligase Activity by Nedd8

  • Raymond J. DeshaiesAffiliated withDivision of Biology, Howard Hughes Medical Institute, California Institute of Technology Email author 
  • , Ethan D. EmberleyAffiliated withDivision of Biology, Howard Hughes Medical Institute, California Institute of Technology
  • , Anjanabha SahaAffiliated withDivision of Biology, Howard Hughes Medical Institute, California Institute of TechnologyOncology, Cancer Research, GlaxoSmithKline

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Abstract

The Cullin-RING ubiquitin ligase (CRL) family, which may number as many as 350 different enzymes, has an enormous impact on cellular regulation. CRL enzymes regulate cell biology by conjugating ubiquitin onto target proteins that are involved in a multitude of processes. In most cases this leads to degradation of the target, but in some cases CRL-dependent ubiquitination acts as a switch to activate or repress target function. The ubiquitin ligase activity of CRLs is controlled by cycles of attachment and removal of the ubiquitin-like protein Nedd8. Conjugation of Nedd8 onto the cullin subunit of CRLs promotes assembly of an intact CRL complex and switches on ubiquitin ligase activity. Conversely, removal of Nedd8 switches off ubiquitin ligase activity and initiates CRL disassembly. Continuous maintenance of CRL function in vivo requires the activities of both the Nedd8-conjugating and deconjugating enzymes, pointing to a critical role of complex dynamics in CRL function. Here, we review how the Nedd8 cycle controls CRL activity and how perturbations of this cycle can lead to disease.