Structure of the A20 OTU domain and mechanistic insights into deubiquitination

Biochem J. 2008 Jan 1;409(1):77-85. doi: 10.1042/BJ20071399.


The NF-kappaB (nuclear factor kappaB) regulator A20 antagonises IKK [IkappaB (inhibitor of kappaB) kinase] activation by modulating Lys63-linked polyubiquitination of cytokine-receptor-associated factors including TRAF2/6 (tumour-necrosis-factor-receptor-associated factor 2/6) and RIP1 (receptor-interacting protein 1). In the present paper we describe the crystal structure of the N-terminal OTU (ovarian tumour) deubiquitinase domain of A20, which differs from other deubiquitinases but shares the minimal catalytic core with otubain-2. Analysis of conserved surface regions allows prediction of ubiquitin-binding sites for the proximal and distal ubiquitin molecules. Structural and biochemical analysis suggests a novel architecture of the catalytic triad, which might be present in a subset of OTU domains including Cezanne and TRABID (TRAF-binding domain). Biochemical analysis shows a preference of the isolated A20 OTU domain for Lys48-linked tetraubiquitin in vitro suggesting that additional specificity factors might be required for the physiological function of A20 in cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Biochemistry / methods
  • Catalysis
  • Catalytic Domain
  • Cloning, Molecular
  • DNA-Binding Proteins
  • Humans
  • I-kappa B Kinase / metabolism*
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Lysine / chemistry
  • Molecular Sequence Data
  • Nuclear Pore Complex Proteins / metabolism
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • Phosphorylation
  • Protein Structure, Tertiary
  • RNA-Binding Proteins / metabolism
  • Thiolester Hydrolases / chemistry*
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Ubiquitin / chemistry*


  • AGFG1 protein, human
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Pore Complex Proteins
  • Nuclear Proteins
  • RNA-Binding Proteins
  • Ubiquitin
  • I-kappa B Kinase
  • OTUB2 protein, human
  • Thiolester Hydrolases
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Lysine

Associated data

  • PDB/2VFJ