The family of ubiquitin-conjugating enzymes (E2s): deciding between life and death of proteins

FASEB J. 2010 Apr;24(4):981-93. doi: 10.1096/fj.09-136259. Epub 2009 Nov 25.


The family of ubiquitin-conjugating (E2) enzymes is characterized by the presence of a highly conserved ubiquitin-conjugating (UBC) domain. These domains accommodate the ATP-activated ubiquitin (Ub) or ubiquitin-like (UBL) protein via a covalently linked thioester onto its active-site residue. E2 enzymes act via selective protein-protein interactions with the E1 and E3 enzymes and connect activation to covalent modification. By doing so, E2s differentiate effects on downstream substrates, either with a single Ub/UBL molecule or as a chain. While E3s are involved in substrate selection, E2s are the main determinants for selection of the lysine to construct ubiquitin chains, which thereby directly control the cellular fate of the substrate. In humans, 35 active E2 enzymes have been identified so far, while other eukaryotic genomes harbor 16 to 35 E2 family members. Some E2s possess N- and/or C-terminal extensions that mediate E2-specific processes. During the past two decades, strong support has led to the control of E2 enzymes in decisions concerning the life or death of a protein. Here, we summarize current knowledge and recent developments on E2 enzymes with respect to structural characteristics and functions. From this we propose a shell-like model to rationalize the selectivity of these key enzymes in directing Ub/UBL-conjugation pathways.-Van Wijk, S. J. L., Timmers, H. T. M. The family of ubiquitin-conjugating enzymes (E2s): deciding between life and death of proteins.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Animals
  • Enzyme Activation / physiology
  • Genome, Human*
  • Humans
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Substrate Specificity / physiology
  • Ubiquitin / metabolism*
  • Ubiquitin-Conjugating Enzymes / chemistry
  • Ubiquitin-Conjugating Enzymes / metabolism*
  • Ubiquitination / physiology*


  • Ubiquitin
  • Adenosine Triphosphate
  • Ubiquitin-Conjugating Enzymes