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PDBsum entry 3vuw
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Protein binding/metal binding protein
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PDB id
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3vuw
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References listed in PDB file
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Key reference
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Title
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Specific recognition of linear polyubiquitin by a20 zinc finger 7 is involved in nf-κB regulation.
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Authors
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F.Tokunaga,
H.Nishimasu,
R.Ishitani,
E.Goto,
T.Noguchi,
K.Mio,
K.Kamei,
A.Ma,
K.Iwai,
O.Nureki.
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Ref.
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Embo J, 2012,
31,
3856-3870.
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PubMed id
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Abstract
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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.
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