Review article

Getting into position: the catalytic mechanisms of protein ubiquitylation



The role of protein ubiquitylation in the control of diverse cellular pathways has recently gained widespread attention. Ubiquitylation not only directs the targeted destruction of tagged proteins by the 26 S proteasome, but it also modulates protein activities, protein–protein interactions and subcellular localization. An understanding of the components involved in protein ubiquitylation (E1s, E2s and E3s) is essential to understand how specificity and regulation are conferred upon these pathways. Much of what we know about the catalytic mechanisms of protein ubiquitylation comes from structural studies of the proteins involved in this process. Indeed, structures of ubiquitin-activating enzymes (E1s) and ubiquitin-conjugating enzymes (E2s) have provided insight into their mechanistic details. E3s (ubiquitin ligases) contain most of the substrate specificity and regulatory elements required for protein ubiquitylation. Although several E3 structures are available, the specific mechanistic role of E3s is still unclear. This review will discuss the different types of ubiquitin signals and how they are generated. Recent advances in the field of protein ubiquitylation will be examined, including the mechanisms of E1, E2 and E3. In particular, we discuss the complexity of molecular recognition required to impose selectivity on substrate selection and topology of poly-ubiquitin chains.

  • E1
  • E2
  • E3
  • ubiquitin
  • post-translational modification
  • RING finger


  • Abbreviations used: APC, anaphase-promoting complex; DUB, deubiquitylating enzyme; E1, ubiquitin-activating enzyme; E2, ubiquitin-conjugating enzyme; E3, ubiquitin ligase; E4, poly-ubiquitin chain conjugation factor; HAT, histone acetyl transferase; HAUSP, herpes-associated ubiquitin-specific protease; HECT, homologous to E6-AP carboxy-terminus; PCNA, proliferating cell nuclear antigen; RING, really interesting new gene; SCF, Skp1-Cdc53/Cul1-F-box protein; SUMO, small ubiqitin-related modifier; UBA, ubiquitin-associated domain; Ubc, ubiquitin-conjugating enzyme; UBL, ubiquitin-like proteins; UBP, ubiquitin binding protein; UEV, ubiquitin E2 variant; UIM, ubiquitin interacting motif.