Molecular Basis for the Unique Deubiquitinating Activity of the NF-κB Inhibitor A20

Su Chang Lin, Jee Y. Chung, Betty Lamothe, Kanagalaghatta Rajashankar, Miao Lu, Yu Chih Lo, Amy Y. Lam, Bryant G. Darnay, Hao Wu

Research output: Contribution to journalArticlepeer-review

120 Citations (Scopus)

Abstract

Nuclear factor κB (NF-κB) 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-κB 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-κB activation in the tumor necrosis factor, interleukin-1, and Toll-like receptor pathways.

Original languageEnglish
Pages (from-to)526-540
Number of pages15
JournalJournal of Molecular Biology
Volume376
Issue number2
DOIs
Publication statusPublished - 2008 Feb 15

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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