| 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]
Publication Abstract from PubMed
In the ubiquitin-proteasome system (UPS), E2 enzymes mediate the conjugation of ubiquitin to substrates and thereby control protein stability and interactions. The E2 enzyme hCdc34 catalyzes the ubiquitination of hundreds of proteins in conjunction with the cullin-RING (CRL) superfamily of E3 enzymes. We identified a small molecule termed CC0651 that selectively inhibits hCdc34. Structure determination revealed that CC0651 inserts into a cryptic binding pocket on hCdc34 distant from the catalytic site, causing subtle but wholesale displacement of E2 secondary structural elements. CC0651 analogs inhibited proliferation of human cancer cell lines and caused accumulation of the SCF(Skp2) substrate p27(Kip1). CC0651 does not affect hCdc34 interactions with E1 or E3 enzymes or the formation of the ubiquitin thioester but instead interferes with the discharge of ubiquitin to acceptor lysine residues. E2 enzymes are thus susceptible to noncatalytic site inhibition and may represent a viable class of drug target in the UPS.
An allosteric inhibitor of the human cdc34 ubiquitin-conjugating enzyme.,Ceccarelli DF, Tang X, Pelletier B, Orlicky S, Xie W, Plantevin V, Neculai D, Chou YC, Ogunjimi A, Al-Hakim A, Varelas X, Koszela J, Wasney GA, Vedadi M, Dhe-Paganon S, Cox S, Xu S, Lopez-Girona A, Mercurio F, Wrana J, Durocher D, Meloche S, Webb DR, Tyers M, Sicheri F Cell. 2011 Jun 24;145(7):1075-87. Epub 2011 Jun 16. PMID:21683433[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Ceccarelli DF, Tang X, Pelletier B, Orlicky S, Xie W, Plantevin V, Neculai D, Chou YC, Ogunjimi A, Al-Hakim A, Varelas X, Koszela J, Wasney GA, Vedadi M, Dhe-Paganon S, Cox S, Xu S, Lopez-Girona A, Mercurio F, Wrana J, Durocher D, Meloche S, Webb DR, Tyers M, Sicheri F. An allosteric inhibitor of the human cdc34 ubiquitin-conjugating enzyme. Cell. 2011 Jun 24;145(7):1075-87. Epub 2011 Jun 16. PMID:21683433 doi:10.1016/j.cell.2011.05.039
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