| Structural highlights
6fga is a 15 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Gene: | TRIM21, RNF81, RO52, SSA1 (HUMAN), UBE2E1, UBCH6 (HUMAN) |
| Activity: | RING-type E3 ubiquitin transferase, with EC number 2.3.2.27 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[RO52_HUMAN] E3 ubiquitin-protein ligase whose activity is dependent on E2 enzymes, UBE2D1, UBE2D2, UBE2E1 and UBE2E2. Forms a ubiquitin ligase complex in cooperation with the E2 UBE2D2 that is used not only for the ubiquitination of USP4 and IKBKB but also for its self-ubiquitination. Component of cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes such as SCF(SKP2)-like complexes. A TRIM21-containing SCF(SKP2)-like complex is shown to mediate ubiquitination of CDKN1B ('Thr-187' phosphorylated-form), thereby promoting its degradation by the proteasome. Monoubiquitinates IKBKB that will negatively regulates Tax-induced NF-kappa-B signaling. Negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. Mediates the ubiquitin-mediated proteasomal degradation of IgG1 heavy chain, which is linked to the VCP-mediated ER-associated degradation (ERAD) pathway. Promotes IRF8 ubiquitination, which enhanced the ability of IRF8 to stimulate cytokine genes transcription in macrophages. Plays a role in the regulation of the cell cycle progression. Enhances the decapping activity of DCP2. Exists as a ribonucleoprotein particle present in all mammalian cells studied and composed of a single polypeptide and one of four small RNA molecules. At least two isoforms are present in nucleated and red blood cells, and tissue specific differences in RO/SSA proteins have been identified. The common feature of these proteins is their ability to bind HY RNAs.2. Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma. Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1 and ATG8 family members and recognizes specific autophagy targets, thus coordinating target recognition with assembly of the autophagic apparatus and initiation of autophagy. Acts as an autophagy receptor for the degradation of IRF3, hence attenuating type I interferon (IFN)-dependent immune responses (PubMed:26347139).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [UB2E1_HUMAN] Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. Catalyzes the covalent attachment of ISG15 to other proteins. Mediates the selective degradation of short-lived and abnormal proteins. In vitro also catalyzes 'Lys-48'-linked polyubiquitination.[11] [12]
Publication Abstract from PubMed
The E3 ubiquitin-protein ligase TRIM21, of the RING-containing tripartite motif (TRIM) protein family, is a major autoantigen in autoimmune diseases and a modulator of innate immune signaling. Together with ubiquitin-conjugating enzyme E2 E1 (UBE2E1), TRIM21 acts both as an E3 ligase and as a substrate in autoubiquitination. We here report a 2.82 A crystal structure of the human TRIM21 RING domain in complex with the human E2-conjugating UBE2E1 enzyme, in which a ubiquitin-targeted TRIM21 substrate lysine was captured in the UBE2E1 active site. The structure revealed that the direction of lysine entry is similar to that described for human proliferating cell nuclear antigen (PCNA), a small ubiquitin-like modifier (SUMO)-targeted substrate, and thus differs from the canonical SUMO-targeted substrate entry. In agreement, we found that critical UBE2E1 residues involved in the capture of the TRIM21 substrate lysine are conserved in ubiquitin-conjugating E2s, whereas residues critical for SUMOylation are not conserved. We noted that coordination of the acceptor lysine leads to remodeling of amino acid side-chain interactions between the UBE2E1 active site and the E2-E3 direct interface, including the so-called "linchpin" residue conserved in RING E3s and required for ubiquitination. The findings of our work support the notion that substrate lysine activation of an E2-E3-connecting allosteric path may trigger catalytic activity and contribute to the understanding of specific lysine targeting by ubiquitin-conjugating E2s.
E3 ubiquitin-protein ligase TRIM21-mediated lysine capture by UBE2E1 reveals substrate-targeting mode of a ubiquitin-conjugating E2.,Anandapadamanaban M, Kyriakidis NC, Csizmok V, Wallenhammar A, Espinosa AC, Ahlner A, Round AR, Trewhella J, Moche M, Wahren-Herlenius M, Sunnerhagen M J Biol Chem. 2019 Jun 3. pii: RA119.008485. doi: 10.1074/jbc.RA119.008485. PMID:31160341[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wada K, Kamitani T. Autoantigen Ro52 is an E3 ubiquitin ligase. Biochem Biophys Res Commun. 2006 Jan 6;339(1):415-21. Epub 2005 Nov 14. PMID:16297862 doi:http://dx.doi.org/10.1016/j.bbrc.2005.11.029
- ↑ Wada K, Tanji K, Kamitani T. Oncogenic protein UnpEL/Usp4 deubiquitinates Ro52 by its isopeptidase activity. Biochem Biophys Res Commun. 2006 Jan 20;339(3):731-6. PMID:16316627 doi:10.1016/j.bbrc.2005.11.076
- ↑ Wada K, Kamitani T. UnpEL/Usp4 is ubiquitinated by Ro52 and deubiquitinated by itself. Biochem Biophys Res Commun. 2006 Mar 31;342(1):253-8. Epub 2006 Feb 6. PMID:16472766 doi:10.1016/j.bbrc.2006.01.144
- ↑ Sabile A, Meyer AM, Wirbelauer C, Hess D, Kogel U, Scheffner M, Krek W. Regulation of p27 degradation and S-phase progression by Ro52 RING finger protein. Mol Cell Biol. 2006 Aug;26(16):5994-6004. PMID:16880511 doi:http://dx.doi.org/10.1128/MCB.01630-05
- ↑ Takahata M, Bohgaki M, Tsukiyama T, Kondo T, Asaka M, Hatakeyama S. Ro52 functionally interacts with IgG1 and regulates its quality control via the ERAD system. Mol Immunol. 2008 Apr;45(7):2045-54. Epub 2007 Nov 26. PMID:18022694 doi:http://dx.doi.org/10.1016/j.molimm.2007.10.023
- ↑ Yamochi T, Ohnuma K, Hosono O, Tanaka H, Kanai Y, Morimoto C. SSA/Ro52 autoantigen interacts with Dcp2 to enhance its decapping activity. Biochem Biophys Res Commun. 2008 May 23;370(1):195-9. doi:, 10.1016/j.bbrc.2008.03.075. Epub 2008 Mar 24. PMID:18361920 doi:http://dx.doi.org/10.1016/j.bbrc.2008.03.075
- ↑ Higgs R, Ni Gabhann J, Ben Larbi N, Breen EP, Fitzgerald KA, Jefferies CA. The E3 ubiquitin ligase Ro52 negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. J Immunol. 2008 Aug 1;181(3):1780-6. PMID:18641315
- ↑ Espinosa A, Oke V, Elfving A, Nyberg F, Covacu R, Wahren-Herlenius M. The autoantigen Ro52 is an E3 ligase resident in the cytoplasm but enters the nucleus upon cellular exposure to nitric oxide. Exp Cell Res. 2008 Dec 10;314(20):3605-13. doi: 10.1016/j.yexcr.2008.09.011. Epub, 2008 Sep 25. PMID:18845142 doi:http://dx.doi.org/10.1016/j.yexcr.2008.09.011
- ↑ Wada K, Niida M, Tanaka M, Kamitani T. Ro52-mediated monoubiquitination of IKK{beta} down-regulates NF-{kappa}B signalling. J Biochem. 2009 Dec;146(6):821-32. doi: 10.1093/jb/mvp127. Epub 2009 Aug 12. PMID:19675099 doi:http://dx.doi.org/10.1093/jb/mvp127
- ↑ Kimura T, Jain A, Choi SW, Mandell MA, Schroder K, Johansen T, Deretic V. TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity. J Cell Biol. 2015 Sep 14;210(6):973-89. PMID:26347139 doi:http://dx.doi.org/10.1083/jcb.201503023
- ↑ Takeuchi T, Iwahara S, Saeki Y, Sasajima H, Yokosawa H. Link between the ubiquitin conjugation system and the ISG15 conjugation system: ISG15 conjugation to the UbcH6 ubiquitin E2 enzyme. J Biochem. 2005 Dec;138(6):711-9. PMID:16428300 doi:10.1093/jb/mvi172
- ↑ 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
- ↑ Anandapadamanaban M, Kyriakidis NC, Csizmok V, Wallenhammar A, Espinosa AC, Ahlner A, Round AR, Trewhella J, Moche M, Wahren-Herlenius M, Sunnerhagen M. E3 ubiquitin-protein ligase TRIM21-mediated lysine capture by UBE2E1 reveals substrate-targeting mode of a ubiquitin-conjugating E2. J Biol Chem. 2019 Jun 3. pii: RA119.008485. doi: 10.1074/jbc.RA119.008485. PMID:31160341 doi:http://dx.doi.org/10.1074/jbc.RA119.008485
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