Deubiquitinating Enzymes: A New Class of Biological Regulators

Protein ubiquitination controls many intracellular processes, including cell cycle progression, transcriptional activation, and signal transduction. Like protein phosphorylation, protein ubiquitination is dynamic, involving enzymes that add ubiquitin (ubiquitin conjugating enzymes) and enzymes that remove ubiquitin (deubiquitinating enzymes). Considerable progress has been made in the understanding of ubiquitin conjugation and its role in regulating protein degradation. Recent studies have demonstrated that regulation also occurs at the level of deubiquitination. Deubiquitinating enzymes are cysteine proteases that specifically cleave ubiquitin from ubiquitin-conjugated protein substrates. Genome sequencing projects have identified many candidate deubiquitinating enzymes, making them the largest family of enzymes in the ubiquitin system. Deubiquitinating enzymes have significant sequence diversity and therefore may have a broad range of substrate specificities. Here we explore the structural and biochemical properties of deubiquitinating enzymes and their emerging roles as cellular switches.