| Structural highlights
Function
UB2D2_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 autoubiquitination of STUB1 and TRAF6. Involved in the signal-induced conjugation and subsequent degradation of NFKBIA, FBXW2-mediated GCM1 ubiquitination and degradation, MDM2-dependent degradation of p53/TP53 and the activation of MAVS in the mitochondria by DDX58/RIG-I in response to viral infection. Essential for viral activation of IRF3.[1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
The conjugation of ubiquitin (Ub) or ubiquitin-like proteins (UBL) to target proteins is a crucial post-translational modification that typically involves nucleophilic attack by a lysine on a charged E2 enzyme (E2~Ub/UBL), forming an oxyanion intermediate. Stabilizing this intermediate through an oxyanion hole is vital for progression of the reaction. Still, the mechanism of oxyanion stabilization in E2 enzymes remains unclear, although an asparagine residue in the conserved HPN motif of E2 enzymes was suggested to stabilize the oxyanion intermediate. Here, we study the E2 enzyme UFC1, which presents a TAK rather than an HPN motif. Crystal structures of UFC1 mutants, including one that mimics the oxyanion intermediate, combined with in vitro activity assays, suggest that UFC1 utilizes two distinct types of oxyanion holes, one that stabilizes the oxyanion intermediate during trans-ufmylation mediated by the E3 ligase, and another that stabilizes cis-driven auto-ufmylation. Our findings indicate that oxyanion stabilization is influenced by multiple factors, including C-alpha hydrogen bonding, and is adaptable, enabling different modes of action.
UFC1 reveals the multifactorial and plastic nature of oxyanion holes in E2 conjugating enzymes.,Kumar M, Banerjee S, Cohen-Kfir E, Mitelberg MB, Tiwari S, Isupov MN, Dessau M, Wiener R Nat Commun. 2025 Apr 25;16(1):3912. doi: 10.1038/s41467-025-58826-y. PMID:40280917[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Gonen H, Bercovich B, Orian A, Carrano A, Takizawa C, Yamanaka K, Pagano M, Iwai K, Ciechanover A. Identification of the ubiquitin carrier proteins, E2s, involved in signal-induced conjugation and subsequent degradation of IkappaBalpha. J Biol Chem. 1999 May 21;274(21):14823-30. PMID:10329681
- ↑ Saville MK, Sparks A, Xirodimas DP, Wardrop J, Stevenson LF, Bourdon JC, Woods YL, Lane DP. Regulation of p53 by the ubiquitin-conjugating enzymes UbcH5B/C in vivo. J Biol Chem. 2004 Oct 1;279(40):42169-81. Epub 2004 Jul 26. PMID:15280377 doi:10.1074/jbc.M403362200
- ↑ 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
- ↑ Chiang MH, Chen LF, Chen H. Ubiquitin-conjugating enzyme UBE2D2 is responsible for FBXW2 (F-box and WD repeat domain containing 2)-mediated human GCM1 (glial cell missing homolog 1) ubiquitination and degradation. Biol Reprod. 2008 Nov;79(5):914-20. doi: 10.1095/biolreprod.108.071407. Epub 2008, Aug 13. PMID:18703417 doi:10.1095/biolreprod.108.071407
- ↑ 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
- ↑ 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
- ↑ Zeng W, Sun L, Jiang X, Chen X, Hou F, Adhikari A, Xu M, Chen ZJ. Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell. 2010 Apr 16;141(2):315-30. doi: 10.1016/j.cell.2010.03.029. PMID:20403326 doi:10.1016/j.cell.2010.03.029
- ↑ 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
- ↑ Kumar M, Banerjee S, Cohen-Kfir E, Mitelberg MB, Tiwari S, Isupov MN, Dessau M, Wiener R. UFC1 reveals the multifactorial and plastic nature of oxyanion holes in E2 conjugating enzymes. Nat Commun. 2025 Apr 25;16(1):3912. PMID:40280917 doi:10.1038/s41467-025-58826-y
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