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3oj4

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Crystal structure of the A20 ZnF4, ubiquitin and UbcH5A complex

Structural highlights

3oj4 is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.4Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

UB2D1_HUMAN Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-linked polyubiquitination. Mediates the selective degradation of short-lived and abnormal proteins. Functions in the E6/E6-AP-induced ubiquitination of p53/TP53. Mediates ubiquitination of PEX5 and auto-ubiquitination of STUB1, TRAF6 and TRIM63/MURF1. Ubiquitinates STUB1-associated HSP90AB1 in vitro. Lacks inherent specificity for any particular lysine residue of ubiquitin. Essential for viral activation of IRF3. Mediates polyubiquitination of CYP3A4.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Inactivating 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^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Windheim M, Peggie M, Cohen P. Two different classes of E2 ubiquitin-conjugating enzymes are required for the mono-ubiquitination of proteins and elongation by polyubiquitin chains with a specific topology. Biochem J. 2008 Feb 1;409(3):723-9. PMID:18042044 doi:10.1042/BJ20071338
↑ Grou CP, Carvalho AF, Pinto MP, Wiese S, Piechura H, Meyer HE, Warscheid B, Sa-Miranda C, Azevedo JE. Members of the E2D (UbcH5) family mediate the ubiquitination of the conserved cysteine of Pex5p, the peroxisomal import receptor. J Biol Chem. 2008 May 23;283(21):14190-7. doi: 10.1074/jbc.M800402200. Epub 2008 , Mar 22. PMID:18359941 doi:10.1074/jbc.M800402200
↑ Pabarcus MK, Hoe N, Sadeghi S, Patterson C, Wiertz E, Correia MA. CYP3A4 ubiquitination by gp78 (the tumor autocrine motility factor receptor, AMFR) and CHIP E3 ligases. Arch Biochem Biophys. 2009 Mar 1;483(1):66-74. doi: 10.1016/j.abb.2008.12.001., Epub 2008 Dec 10. PMID:19103148 doi:10.1016/j.abb.2008.12.001
↑ Zeng W, Xu M, Liu S, Sun L, Chen ZJ. Key role of Ubc5 and lysine-63 polyubiquitination in viral activation of IRF3. Mol Cell. 2009 Oct 23;36(2):315-25. doi: 10.1016/j.molcel.2009.09.037. PMID:19854139 doi:10.1016/j.molcel.2009.09.037
↑ David Y, Ziv T, Admon A, Navon A. The E2 ubiquitin conjugating enzymes direct polyubiquitination to preferred lysines. J Biol Chem. 2010 Jan 8. PMID:20061386 doi:M109.089003
↑ 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. Ubiquitin Binding to A20 ZnF4 Is Required for Modulation of NF-kappaB Signaling. Mol Cell. 2010 Nov 24;40(4):548-57. PMID:21095585 doi:10.1016/j.molcel.2010.10.009