3VUW

Crystal structure of A20 ZF7 in complex with linear ubiquitin, form I

Summary for 3VUW

• Entry DOI: 10.2210/pdb3vuw/pdb
• Related: 3VUX 3VUY
• Descriptor: Polyubiquitin-C, Tumor necrosis factor alpha-induced protein 3, ZINC ION, ... (5 entities in total)
• Functional Keywords: zinc finger, cellular signaling, ubiquitination, protein binding-metal binding protein complex, protein binding/metal binding protein
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm. A20p50: Cytoplasm: P0CG48; Ubiquitin: Cytoplasm (By similarity): P21580
• Total number of polymer chains: 6
• Total formula weight: 37802.51

Authors

Nishimasu, H.,Ishitani, R.,Nureki, O. (deposition date: 2012-07-09, release date: 2013-02-13, Last modification date: 2024-03-20)

Primary citation

Tokunaga, F.,Nishimasu, H.,Ishitani, R.,Goto, E.,Noguchi, T.,Mio, K.,Kamei, K.,Ma, A.,Iwai, K.,Nureki, O.
Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-kappaB regulation
Embo J., 31:3856-3870, 2012

PubMed Abstract: LUBAC (linear ubiquitin chain assembly complex) activates the canonical NF-κB pathway through linear polyubiquitination of NEMO (NF-κB essential modulator, also known as IKKγ) and RIP1. However, the regulatory mechanism of LUBAC-mediated NF-κB activation remains elusive. Here, we show that A20 suppresses LUBAC-mediated NF-κB activation by binding linear polyubiquitin via the C-terminal seventh zinc finger (ZF7), whereas CYLD suppresses it through deubiquitinase (DUB) activity. We determined the crystal structures of A20 ZF7 in complex with linear diubiquitin at 1.70-1.98 Å resolutions. The crystal structures revealed that A20 ZF7 simultaneously recognizes the Met1-linked proximal and distal ubiquitins, and that genetic mutations associated with B cell lymphomas map to the ubiquitin-binding sites. Our functional analysis indicated that the binding of A20 ZF7 to linear polyubiquitin contributes to the recruitment of A20 into a TNF receptor (TNFR) signalling complex containing LUBAC and IκB kinase (IKK), which results in NF-κB suppression. These findings provide new insight into the regulation of immune and inflammatory responses.

PubMed: 23032187
DOI: 10.1038/emboj.2012.241

Experimental method

X-RAY DIFFRACTION (1.95 Å)