Ubiquitin-like Protein Conjugation: Structures, Chemistry, and Mechanism

Chem Rev. 2018 Feb 14;118(3):889-918. doi: 10.1021/acs.chemrev.6b00737. Epub 2017 Feb 24.


Ubiquitin-like proteins (Ubl's) are conjugated to target proteins or lipids to regulate their activity, stability, subcellular localization, or macromolecular interactions. Similar to ubiquitin, conjugation is achieved through a cascade of activities that are catalyzed by E1 activating enzymes, E2 conjugating enzymes, and E3 ligases. In this review, we will summarize structural and mechanistic details of enzymes and protein cofactors that participate in Ubl conjugation cascades. Precisely, we will focus on conjugation machinery in the SUMO, NEDD8, ATG8, ATG12, URM1, UFM1, FAT10, and ISG15 pathways while referring to the ubiquitin pathway to highlight common or contrasting themes. We will also review various strategies used to trap intermediates during Ubl activation and conjugation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Catalytic Domain
  • Humans
  • NEDD8 Protein / chemistry
  • NEDD8 Protein / metabolism
  • Small Ubiquitin-Related Modifier Proteins / chemistry
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Substrate Specificity
  • Ubiquitin / chemistry
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism


  • NEDD8 Protein
  • Small Ubiquitin-Related Modifier Proteins
  • Ubiquitin
  • Ubiquitin-Protein Ligases