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

Journal Article · Tue Jan 01 04:00:00 EST 2008 · Journal of Molecular Biology

DOI:https://doi.org/10.1016/j.jmb.2007.11.092· OSTI ID:980348

Lin, S; Chung, J; Lamothe, B; Rajashankar, K; Lu, M; Lo, Y; Lam, A; Darnay, B; Wu, H

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

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 980348
• Report Number(s): BNL--93266-2010-JA
• Journal Information: Journal of Molecular Biology, Journal Name: Journal of Molecular Biology Vol. 376; ISSN JMOBAK; ISSN 0022-2836
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
CHAINS
CRYSTAL STRUCTURE
CYSTEINE
ENZYMES
FEEDBACK
LIGASES
SPECIFICITY
SUBSTRATES
national synchrotron light source