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Crystal structure of the A20 ZnF4, ubiquitin and UbcH5A complexCrystal structure of the A20 ZnF4, ubiquitin and UbcH5A complex
Structural highlights
Publication Abstract from PubMedInactivating mutations in the ubiquitin (Ub) editing protein A20 promote persistent nuclear factor (NF)-kappaB signaling and are genetically linked to inflammatory diseases and hematologic cancers. A20 tightly regulates NF-kappaB signaling by acting as an Ub editor, removing K63-linked Ub chains and mediating addition of Ub chains that target substrates for degradation. However, a precise molecular understanding of how A20 modulates this pathway remains elusive. Here, using structural analysis, domain mapping, and functional assays, we show that A20 zinc finger 4 (ZnF4) does not directly interact with E2 enzymes but instead can bind mono-Ub and K63-linked poly-Ub. Mutations to the A20 ZnF4 Ub-binding surface result in decreased A20-mediated ubiquitination and impaired regulation of NF-kappaB signaling. Collectively, our studies illuminate the mechanistically distinct but biologically interdependent activities of the A20 ZnF and ovarian tumor (OTU) domains that are inherent to the Ub editing process and, ultimately, to regulation of NF-kappaB signaling. Ubiquitin Binding to A20 ZnF4 Is Required for Modulation of NF-kappaB Signaling.,Bosanac I, Wertz IE, Pan B, Yu C, Kusam S, Lam C, Phu L, Phung Q, Maurer B, Arnott D, Kirkpatrick DS, Dixit VM, Hymowitz SG Mol Cell. 2010 Nov 24;40(4):548-57. PMID:21095585[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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