| Structural highlights
Function
[OTU7B_HUMAN] Negative regulator of the non-canonical NF-kappa-B pathway that acts by mediating deubiquitination of TRAF3, an inhibitor of the NF-kappa-B pathway, thereby acting as a negative regulator of B-cell responses. In response to non-canonical NF-kappa-B stimuli, deubiquitinates 'Lys-48'-linked polyubiquitin chains of TRAF3, preventing TRAF3 proteolysis and over-activation of non-canonical NF-kappa-B. Negatively regulates mucosal immunity against infections. Mediates deubiquitination of EGFR. Has deubiquitinating activity toward 'Lys-11', 'Lys-48' or 'Lys-63'-linked polyubiquitin chains. In vitro, has preference for 'Lys-11'-linked polyubiquitin chains; however such data are unsure in vivo. Hydrolyzes both linear and branched forms of polyubiquitin.[1] [2] [3] [4] [5] [6] [UBB_HUMAN] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.[7] [8]
Publication Abstract from PubMed
The post-translational modification of proteins with polyubiquitin regulates virtually all aspects of cell biology. Eight distinct chain linkage types co-exist in polyubiquitin and are independently regulated in cells. This 'ubiquitin code' determines the fate of the modified protein. Deubiquitinating enzymes of the ovarian tumour (OTU) family regulate cellular signalling by targeting distinct linkage types within polyubiquitin, and understanding their mechanisms of linkage specificity gives fundamental insights into the ubiquitin system. Here we reveal how the deubiquitinase Cezanne (also known as OTUD7B) specifically targets Lys11-linked polyubiquitin. Crystal structures of Cezanne alone and in complex with monoubiquitin and Lys11-linked diubiquitin, in combination with hydrogen-deuterium exchange mass spectrometry, enable us to reconstruct the enzymatic cycle in great detail. An intricate mechanism of ubiquitin-assisted conformational changes activates the enzyme, and while all chain types interact with the enzymatic S1 site, only Lys11-linked chains can bind productively across the active site and stimulate catalytic turnover. Our work highlights the plasticity of deubiquitinases and indicates that new conformational states can occur when a true substrate, such as diubiquitin, is bound at the active site.
Molecular basis of Lys11-polyubiquitin specificity in the deubiquitinase Cezanne.,Mevissen TE, Kulathu Y, Mulder MP, Geurink PP, Maslen SL, Gersch M, Elliott PR, Burke JE, van Tol BD, Akutsu M, El Oualid F, Kawasaki M, Freund SM, Ovaa H, Komander D Nature. 2016 Oct 12;538(7625):402-405. doi: 10.1038/nature19836. PMID:27732584[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Evans PC, Taylor ER, Coadwell J, Heyninck K, Beyaert R, Kilshaw PJ. Isolation and characterization of two novel A20-like proteins. Biochem J. 2001 Aug 1;357(Pt 3):617-23. PMID:11463333
- ↑ Evans PC, Smith TS, Lai MJ, Williams MG, Burke DF, Heyninck K, Kreike MM, Beyaert R, Blundell TL, Kilshaw PJ. A novel type of deubiquitinating enzyme. J Biol Chem. 2003 Jun 20;278(25):23180-6. Epub 2003 Apr 7. PMID:12682062 doi:http://dx.doi.org/10.1074/jbc.M301863200
- ↑ Enesa K, Zakkar M, Chaudhury H, Luong le A, Rawlinson L, Mason JC, Haskard DO, Dean JL, Evans PC. NF-kappaB suppression by the deubiquitinating enzyme Cezanne: a novel negative feedback loop in pro-inflammatory signaling. J Biol Chem. 2008 Mar 14;283(11):7036-45. doi: 10.1074/jbc.M708690200. Epub 2008 , Jan 4. PMID:18178551 doi:http://dx.doi.org/10.1074/jbc.M708690200
- ↑ Bremm A, Freund SM, Komander D. Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne. Nat Struct Mol Biol. 2010 Aug;17(8):939-47. Epub 2010 Jul 11. PMID:20622874 doi:10.1038/nsmb.1873
- ↑ Pareja F, Ferraro DA, Rubin C, Cohen-Dvashi H, Zhang F, Aulmann S, Ben-Chetrit N, Pines G, Navon R, Crosetto N, Kostler W, Carvalho S, Lavi S, Schmitt F, Dikic I, Yakhini Z, Sinn P, Mills GB, Yarden Y. Deubiquitination of EGFR by Cezanne-1 contributes to cancer progression. Oncogene. 2012 Oct 25;31(43):4599-608. doi: 10.1038/onc.2011.587. Epub 2011 Dec, 19. PMID:22179831 doi:http://dx.doi.org/10.1038/onc.2011.587
- ↑ Mevissen TE, Hospenthal MK, Geurink PP, Elliott PR, Akutsu M, Arnaudo N, Ekkebus R, Kulathu Y, Wauer T, El Oualid F, Freund SM, Ovaa H, Komander D. OTU Deubiquitinases Reveal Mechanisms of Linkage Specificity and Enable Ubiquitin Chain Restriction Analysis. Cell. 2013 Jul 3;154(1):169-84. doi: 10.1016/j.cell.2013.05.046. PMID:23827681 doi:10.1016/j.cell.2013.05.046
- ↑ Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell. 2006 Mar 17;21(6):737-48. PMID:16543144 doi:S1097-2765(06)00120-1
- ↑ Komander D. The emerging complexity of protein ubiquitination. Biochem Soc Trans. 2009 Oct;37(Pt 5):937-53. doi: 10.1042/BST0370937. PMID:19754430 doi:10.1042/BST0370937
- ↑ Mevissen TE, Kulathu Y, Mulder MP, Geurink PP, Maslen SL, Gersch M, Elliott PR, Burke JE, van Tol BD, Akutsu M, El Oualid F, Kawasaki M, Freund SM, Ovaa H, Komander D. Molecular basis of Lys11-polyubiquitin specificity in the deubiquitinase Cezanne. Nature. 2016 Oct 12;538(7625):402-405. doi: 10.1038/nature19836. PMID:27732584 doi:http://dx.doi.org/10.1038/nature19836
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