3DKB

Crystal Structure of A20, 2.5 angstrom

Summary for 3DKB

• Entry DOI: 10.2210/pdb3dkb/pdb
• Descriptor: Tumor necrosis factor, alpha-induced protein 3 (1 entity in total)
• Functional Keywords: otu domain, dub domain, apoptosis, cytoplasm, dna-binding, hydrolase, metal-binding, nucleus, phosphoprotein, polymorphism, protease, thiol protease, ubl conjugation pathway, zinc, zinc-finger
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm. A20p50: Cytoplasm: P21580
• Total number of polymer chains: 6
• Total formula weight: 274015.38

Authors

Lin, S.-C.,Chung, J.Y.,Lo, Y.-C.,Wu, H. (deposition date: 2008-06-24, release date: 2008-07-08, Last modification date: 2024-02-21)

Primary citation

Lin, S.-C.,Chung, J.Y.,Lamothe, B.,Rajashankar, K.,Lu, M.,Lo, Y.-C.,Lam, A.Y.,Darnay, B.G.,Wu, H.
Molecular basis for the unique deubiquitinating activity of the NF-kappaB inhibitor A20
J.Mol.Biol., 376:526-540, 2008

PubMed Abstract: 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: 18164316
DOI: 10.1016/j.jmb.2007.11.092

Experimental method

X-RAY DIFFRACTION (2.5 Å)