| Structural highlights
Function
UB2R1_HUMAN Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-linked polyubiquitination. Cooperates with the E2 UBCH5C and the SCF(FBXW11) E3 ligase complex for the polyubiquitination of NFKBIA leading to its subsequent proteasomal degradation. Performs ubiquitin chain elongation building ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin. UBE2D3 acts as an initiator E2, priming the phosphorylated NFKBIA target at positions 'Lys-21' and/or 'Lys-22' with a monoubiquitin. Cooperates with the SCF(SKP2) E3 ligase complex to regulate cell proliferation through ubiquitination and degradation of MYBL2 and KIP1. Involved in ubiquitin conjugation and degradation of CREM isoform ICERIIgamma and ATF15 resulting in abrogation of ICERIIgamma- and ATF5-mediated repression of cAMP-induced transcription during both meiotic and mitotic cell cycles. Involved in the regulation of the cell cycle G2/M phase through its targeting of the WEE1 kinase for ubiquitination and degradation. Also involved in the degradation of beta-catenin. Is target of human herpes virus 1 protein ICP0, leading to ICP0-dependent dynamic interaction with proteasomes.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Here we describe a systematic structure-function analysis of the human ubiquitin (Ub) E2 conjugating proteins, consisting of the determination of 15 new high-resolution three-dimensional structures of E2 catalytic domains, and autoubiquitylation assays for 26 Ub-loading E2s screened against a panel of nine different HECT (homologous to E6-AP carboxyl terminus) E3 ligase domains. Integration of our structural and biochemical data revealed several E2 surface properties associated with Ub chain building activity; (1) net positive or neutral E2 charge, (2) an "acidic trough" located near the catalytic Cys, surrounded by an extensive basic region, and (3) similarity to the previously described HECT binding signature in UBE2L3 (UbcH7). Mass spectrometry was used to characterize the autoubiquitylation products of a number of functional E2-HECT pairs, and demonstrated that HECT domains from different subfamilies catalyze the formation of very different types of Ub chains, largely independent of the E2 in the reaction. Our data set represents the first comprehensive analysis of E2-HECT E3 interactions, and thus provides a framework for better understanding the molecular mechanisms of ubiquitylation.
A human ubiquitin conjugating enzyme (E2)-HECT E3 ligase structure-function screen.,Sheng Y, Hong JH, Doherty R, Srikumar T, Shloush J, Avvakumov GV, Walker JR, Xue S, Neculai D, Wan JW, Kim SK, Arrowsmith CH, Raught B, Dhe-Paganon S Mol Cell Proteomics. 2012 Aug;11(8):329-41. Epub 2012 Apr 10. PMID:22496338[13]
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
- ↑ Pati D, Meistrich ML, Plon SE. Human Cdc34 and Rad6B ubiquitin-conjugating enzymes target repressors of cyclic AMP-induced transcription for proteolysis. Mol Cell Biol. 1999 Jul;19(7):5001-13. PMID:10373550
- ↑ Charrasse S, Carena I, Brondani V, Klempnauer KH, Ferrari S. Degradation of B-Myb by ubiquitin-mediated proteolysis: involvement of the Cdc34-SCF(p45Skp2) pathway. Oncogene. 2000 Jun 15;19(26):2986-95. PMID:10871850 doi:10.1038/sj.onc.1203618
- ↑ Wu K, Chen A, Tan P, Pan ZQ. The Nedd8-conjugated ROC1-CUL1 core ubiquitin ligase utilizes Nedd8 charged surface residues for efficient polyubiquitin chain assembly catalyzed by Cdc34. J Biol Chem. 2002 Jan 4;277(1):516-27. Epub 2001 Oct 23. PMID:11675391 doi:10.1074/jbc.M108008200
- ↑ Semplici F, Meggio F, Pinna LA, Oliviero S. CK2-dependent phosphorylation of the E2 ubiquitin conjugating enzyme UBC3B induces its interaction with beta-TrCP and enhances beta-catenin degradation. Oncogene. 2002 Jun 6;21(25):3978-87. PMID:12037680 doi:10.1038/sj.onc.1205574
- ↑ Butz N, Ruetz S, Natt F, Hall J, Weiler J, Mestan J, Ducarre M, Grossenbacher R, Hauser P, Kempf D, Hofmann F. The human ubiquitin-conjugating enzyme Cdc34 controls cellular proliferation through regulation of p27Kip1 protein levels. Exp Cell Res. 2005 Feb 15;303(2):482-93. PMID:15652359 doi:10.1016/j.yexcr.2004.10.008
- ↑ Sadowski M, Mawson A, Baker R, Sarcevic B. Cdc34 C-terminal tail phosphorylation regulates Skp1/cullin/F-box (SCF)-mediated ubiquitination and cell cycle progression. Biochem J. 2007 Aug 1;405(3):569-81. PMID:17461777 doi:10.1042/BJ20061812
- ↑ Gazdoiu S, Yamoah K, Wu K, Pan ZQ. Human Cdc34 employs distinct sites to coordinate attachment of ubiquitin to a substrate and assembly of polyubiquitin chains. Mol Cell Biol. 2007 Oct;27(20):7041-52. Epub 2007 Aug 13. PMID:17698585 doi:10.1128/MCB.00812-07
- ↑ Kleiger G, Saha A, Lewis S, Kuhlman B, Deshaies RJ. Rapid E2-E3 assembly and disassembly enable processive ubiquitylation of cullin-RING ubiquitin ligase substrates. Cell. 2009 Nov 25;139(5):957-68. PMID:19945379 doi:S0092-8674(09)01356-7
- ↑ Legesse-Miller A, Elemento O, Pfau SJ, Forman JJ, Tavazoie S, Coller HA. let-7 Overexpression leads to an increased fraction of cells in G2/M, direct down-regulation of Cdc34, and stabilization of Wee1 kinase in primary fibroblasts. J Biol Chem. 2009 Mar 13;284(11):6605-9. doi: 10.1074/jbc.C900002200. Epub 2009, Jan 6. PMID:19126550 doi:10.1074/jbc.C900002200
- ↑ 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
- ↑ Wu K, Kovacev J, Pan ZQ. Priming and extending: a UbcH5/Cdc34 E2 handoff mechanism for polyubiquitination on a SCF substrate. Mol Cell. 2010 Mar 26;37(6):784-96. doi: 10.1016/j.molcel.2010.02.025. PMID:20347421 doi:10.1016/j.molcel.2010.02.025
- ↑ Sheng Y, Hong JH, Doherty R, Srikumar T, Shloush J, Avvakumov GV, Walker JR, Xue S, Neculai D, Wan JW, Kim SK, Arrowsmith CH, Raught B, Dhe-Paganon S. A human ubiquitin conjugating enzyme (E2)-HECT E3 ligase structure-function screen. Mol Cell Proteomics. 2012 Aug;11(8):329-41. Epub 2012 Apr 10. PMID:22496338 doi:http://dx.doi.org/10.1074/mcp.O111.013706
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