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Molecular basis for the unique deubiquitinating activity of the NF-kappaB inhibitor A20.

Nuclear factor kappaB (NF-kappaB) activation in tumor necrosis factor, interleukin-1, and Toll-like receptor pathways requires Lys63-linked nondegradative polyubiquitination. A20 is a specific feedback inhibitor of NF-kappaB activation in these pathways that possesses dual ubiquitin-editing functions. While the N-terminal domain of A20 is a deubiquitinating enzyme (DUB) for Lys63-linked polyubiquitinated signaling mediators such as TRAF6 and RIP, its C-terminal domain is a ubiquitin ligase (E3) for Lys48-linked degradative polyubiquitination of the same substrates. To elucidate the molecular basis for the DUB activity of A20, we determined its crystal structure and performed a series of biochemical and cell biological studies. The structure reveals the potential catalytic mechanism of A20, which may be significantly different from papain-like cysteine proteases. Ubiquitin can be docked onto a conserved A20 surface; this interaction exhibits charge complementarity and no steric clash. Surprisingly, A20 does not have specificity for Lys63-linked polyubiquitin chains. Instead, it effectively removes Lys63-linked polyubiquitin chains from TRAF6 without dissembling the chains themselves. Our studies suggest that A20 does not act as a general DUB but has the specificity for particular polyubiquitinated substrates to assure its fidelity in regulating NF-kappaB activation in the tumor necrosis factor, interleukin-1, and Toll-like receptor pathways.

Pubmed ID: 18164316

Authors

  • Lin SC
  • Chung JY
  • Lamothe B
  • Rajashankar K
  • Lu M
  • Lo YC
  • Lam AY
  • Darnay BG
  • Wu H

Journal

Journal of molecular biology

Publication Data

February 15, 2008

Associated Grants

  • Agency: NIAID NIH HHS, Id: R01 AI045937
  • Agency: NIAID NIH HHS, Id: R01 AI045937
  • Agency: NIAID NIH HHS, Id: R01 AI045937-07
  • Agency: NIAMS NIH HHS, Id: R01 AR053540
  • Agency: NCRR NIH HHS, Id: RR-15301

Mesh Terms

  • Alanine
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Binding Sites
  • Catalysis
  • Cell Line
  • Conserved Sequence
  • Crystallography, X-Ray
  • DNA-Binding Proteins
  • Escherichia coli
  • Gene Deletion
  • Glutathione Transferase
  • Humans
  • Hydrogen Bonding
  • Intracellular Signaling Peptides and Proteins
  • Kidney
  • Models, Molecular
  • Molecular Sequence Data
  • NF-kappa B
  • Nuclear Proteins
  • Polyubiquitin
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Static Electricity
  • Substrate Specificity
  • TNF Receptor-Associated Factor 6
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • Ubiquitination