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CDC34  -  SCF E2 ubiquitin-protein ligase catalytic...

Saccharomyces cerevisiae S288c

Synonyms: Cell division control protein 34, D4211, DNA6, E3 ubiquitin ligase complex SCF subunit CDC34, UBC3, ...
 
 
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Disease relevance of CDC34

  • The recombinant yeast RAD6 and CDC34 gene products were expressed in Escherichia coli extracts and purified to apparent homogeneity [1].
  • Using yeast cells, we searched for the genes involved in the expression of methylmercury toxicity, and found that genes encoding L-glutamine.D-fructose-6-phosphate amidotransferase (GFAT) and ubiquitin transferase (Ubc3) confer methylmercury resistance on the cells [2].
 

High impact information on CDC34

  • Biochemical reconstitution with purified Sic1, a prototype substrate of the Cdc34/SCF ubiquitin ligase, suggests that substrate degradation is essential for triggering the ATP hydrolysis-dependent dissociation and disassembly of the 19S and that this mechanism leads to release of degradation products [3].
  • In contrast, we found that the formation of a ubiquitin thiol ester regulates the Cdc34/SCF(Cdc4) binding equilibrium by increasing the dissociation rate constant, with only a minor effect on the association rate [4].
  • However, transcriptional repression of Met4 target genes correlates with Cdc34/SCF(Met30)-dependent ubiquitination of Met4 [5].
  • A sextuple clb1-6 mutant arrests as multibudded G1 cells that resemble cells lacking the Cdc34 ubiquitin-conjugating enzyme. cdc34 mutants cannot enter S phase because they fail to destroy p40SIC1, which is a potent inhibitor of Clb but not Cln forms of the Cdc28 kinase [6].
  • The Cdc34 ubiquitin-conjugating activity may function redundantly with Ubc9, or it may only be involved in Cln1,2 turnover through its role in promoting the degradation of Sic1, a specific inhibitor of Cdc28-Clb complexes [7].
 

Biological context of CDC34

  • We show that although a catalytic domain is essential for CDC34 activity, a major cell cycle determinant of this enzyme is found within a 74 residue segment of the tail that does not include the polyacidic stretch or downstream sequences [8].
  • Expression of the CDC34 catalytic domain and tail as separate polypeptides are capable of only partial function; thus, while the tail displays autonomous structural characteristics, there is considerable advantage gained when both domains coexist within the same polypeptide [8].
  • Despite this similarity, the CDC34 catalytic domain cannot substitute for the DNA repair and growth functions of the RAD6 catalytic domain, indicating that although these domains are structurally related, sufficient differences exist to maintain their functional individuality [8].
  • Overexpression of yeast CDC34 specifically suppresses the temperature-sensitive growth phenotype of the ndc10-1 mutation [9].
  • These data suggest that Cbf2p is an endogenous substrate of the CDC34 ubiquitin-conjugating enzyme and imply that ubiquitination of a kinetochore protein plays a regulatory role in kinetochore function [9].
 

Anatomical context of CDC34

  • Like their reticulocyte counterparts, RAD6 and CDC34 are bifunctional enzymes competent in both ubiquitin:protein ligase (E3)-independent and E3-dependent conjugation reactions [1].
  • This led us to uncover a role for the Cdc34/SCF complex in the regulation of cell wall integrity [10].
 

Associations of CDC34 with chemical compounds

 

Physical interactions of CDC34

  • Consistent with this prediction, we have shown by chemical cross-linking the existence of a specific noncovalent Ub binding site on CDC34 [16].
  • Cdc53 contains independent binding sites for Cdc34 and Skp1 suggesting it functions as a scaffold protein within an E2/E3 core complex [17].
 

Enzymatic interactions of CDC34

  • Purified Cdc34p catalyzes the formation of Cbf2p-monoubiquitin conjugate in vitro [9].
  • The Ubc3 (Cdc34) enzyme has previously been shown to catalyze the attachment of multiple ubiquitin molecules to model substrates, suggesting that the role of this enzyme in cell cycle progression depends on its targeting an endogenous protein(s) for degradation [18].
  • The autoubiquitination of each F-box was in some cases catalyzed only by Cdc34, and in other cases preferentially catalyzed by Ubc4 [19].
 

Regulatory relationships of CDC34

  • Taken together with other findings, the allele specificity exhibited by UBS1 expression suggests that Ubs1 regulates Cdc34 by interaction or modification [20].
  • Ub overexpression was found to suppress two other structurally unrelated cdc34 mutations, in addition to the cdc34-2 allele [16].
  • One mutant (cdc34-109, 111, 113A) targeted a 12-residue segment of the Cdc34 protein not found in most other E2s and was unable to complement a cdc34 null mutant at low copy numbers but could complement a null mutant when overexpressed from an induced GAL1 promoter [21].
 

Other interactions of CDC34

  • Wild-type Far1p, but not Far1-22p, was readily ubiquitinated in vitro in a CDC34- and CDC4-dependent manner [22].
  • A screen for genetic interactions with a cdc34 mutation yielded MET30, which encodes an F-box protein [23].
  • Mutations in CDC53 cause a phenotype indistinguishable from those of cdc4 and cdc34 mutations, numerous genetic interactions are seen between these genes, and the encoded proteins are found physically associated in vivo [24].
  • Deletion analysis of SIC1 indicates that the N-terminal 160 residues are both necessary and sufficient to serve as substrate for CDC34-dependent ubiquitination [25].
  • The yeast ubiquitin (Ub) conjugating enzyme CDC34 plays a crucial role in the progression of the cell cycle from the G1 to S phase [16].
 

Analytical, diagnostic and therapeutic context of CDC34

References

  1. Ubiquitin conjugation by the yeast RAD6 and CDC34 gene products. Comparison to their putative rabbit homologs, E2(20K) AND E2(32K). Haas, A.L., Reback, P.B., Chau, V. J. Biol. Chem. (1991) [Pubmed]
  2. Investigation of intracellular factors involved in methylmercury toxicity. Naganuma, A., Furuchi, T., Miura, N., Hwang, G.W., Kuge, S. Tohoku J. Exp. Med. (2002) [Pubmed]
  3. ATP hydrolysis-dependent disassembly of the 26S proteasome is part of the catalytic cycle. Babbitt, S.E., Kiss, A., Deffenbaugh, A.E., Chang, Y.H., Bailly, E., Erdjument-Bromage, H., Tempst, P., Buranda, T., Sklar, L.A., Baumler, J., Gogol, E., Skowyra, D. Cell (2005) [Pubmed]
  4. Release of ubiquitin-charged Cdc34-S - Ub from the RING domain is essential for ubiquitination of the SCF(Cdc4)-bound substrate Sic1. Deffenbaugh, A.E., Scaglione, K.M., Zhang, L., Moore, J.M., Buranda, T., Sklar, L.A., Skowyra, D. Cell (2003) [Pubmed]
  5. Regulation of transcription by ubiquitination without proteolysis: Cdc34/SCF(Met30)-mediated inactivation of the transcription factor Met4. Kaiser, P., Flick, K., Wittenberg, C., Reed, S.I. Cell (2000) [Pubmed]
  6. The B-type cyclin kinase inhibitor p40SIC1 controls the G1 to S transition in S. cerevisiae. Schwob, E., Böhm, T., Mendenhall, M.D., Nasmyth, K. Cell (1994) [Pubmed]
  7. G2 cyclins are required for the degradation of G1 cyclins in yeast. Blondel, M., Mann, C. Nature (1996) [Pubmed]
  8. A chimeric ubiquitin conjugating enzyme that combines the cell cycle properties of CDC34 (UBC3) and the DNA repair properties of RAD6 (UBC2): implications for the structure, function and evolution of the E2s. Silver, E.T., Gwozd, T.J., Ptak, C., Goebl, M., Ellison, M.J. EMBO J. (1992) [Pubmed]
  9. Genetic and biochemical interactions between an essential kinetochore protein, Cbf2p/Ndc10p, and the CDC34 ubiquitin-conjugating enzyme. Yoon, H.J., Carbon, J. Mol. Cell. Biol. (1995) [Pubmed]
  10. The Cdc34/SCF Ubiquitination Complex Mediates Saccharomyces cerevisiae Cell Wall Integrity. Varelas, X., Stuart, D., Ellison, M.J., Ptak, C. Genetics (2006) [Pubmed]
  11. Identification of a portable determinant of cell cycle function within the carboxyl-terminal domain of the yeast CDC34 (UBC3) ubiquitin conjugating (E2) enzyme. Kolman, C.J., Toth, J., Gonda, D.K. EMBO J. (1992) [Pubmed]
  12. Overexpression of the ubiquitin-conjugating enzyme Cdc34 confers resistance to methylmercury in Saccharomyces cerevisiae. Furuchi, T., Hwang, G.W., Naganuma, A. Mol. Pharmacol. (2002) [Pubmed]
  13. Intragenic suppression among CDC34 (UBC3) mutations defines a class of ubiquitin-conjugating catalytic domains. Liu, Y., Mathias, N., Steussy, C.N., Goebl, M.G. Mol. Cell. Biol. (1995) [Pubmed]
  14. Cdc34 self-association is facilitated by ubiquitin thiolester formation and is required for its catalytic activity. Varelas, X., Ptak, C., Ellison, M.J. Mol. Cell. Biol. (2003) [Pubmed]
  15. The bacterially expressed yeast CDC34 gene product can undergo autoubiquitination to form a multiubiquitin chain-linked protein. Banerjee, A., Gregori, L., Xu, Y., Chau, V. J. Biol. Chem. (1993) [Pubmed]
  16. Increased ubiquitin expression suppresses the cell cycle defect associated with the yeast ubiquitin conjugating enzyme, CDC34 (UBC3). Evidence for a noncovalent interaction between CDC34 and ubiquitin. Prendergast, J.A., Ptak, C., Arnason, T.G., Ellison, M.J. J. Biol. Chem. (1995) [Pubmed]
  17. Cdc53 is a scaffold protein for multiple Cdc34/Skp1/F-box proteincomplexes that regulate cell division and methionine biosynthesis in yeast. Patton, E.E., Willems, A.R., Sa, D., Kuras, L., Thomas, D., Craig, K.L., Tyers, M. Genes Dev. (1998) [Pubmed]
  18. The Ubc3 (Cdc34) ubiquitin-conjugating enzyme is ubiquitinated and phosphorylated in vivo. Goebl, M.G., Goetsch, L., Byers, B. Mol. Cell. Biol. (1994) [Pubmed]
  19. Functional interaction of 13 yeast SCF complexes with a set of yeast E2 enzymes in vitro. Kus, B.M., Caldon, C.E., Andorn-Broza, R., Edwards, A.M. Proteins (2004) [Pubmed]
  20. Identification of a positive regulator of the cell cycle ubiquitin-conjugating enzyme Cdc34 (Ubc3). Prendergast, J.A., Ptak, C., Kornitzer, D., Steussy, C.N., Hodgins, R., Goebl, M., Ellison, M.J. Mol. Cell. Biol. (1996) [Pubmed]
  21. Novel CDC34 (UBC3) ubiquitin-conjugating enzyme mutants obtained by charge-to-alanine scanning mutagenesis. Pitluk, Z.W., McDonough, M., Sangan, P., Gonda, D.K. Mol. Cell. Biol. (1995) [Pubmed]
  22. Phosphorylation- and ubiquitin-dependent degradation of the cyclin-dependent kinase inhibitor Far1p in budding yeast. Henchoz, S., Chi, Y., Catarin, B., Herskowitz, I., Deshaies, R.J., Peter, M. Genes Dev. (1997) [Pubmed]
  23. Cdc34 and the F-box protein Met30 are required for degradation of the Cdk-inhibitory kinase Swe1. Kaiser, P., Sia, R.A., Bardes, E.G., Lew, D.J., Reed, S.I. Genes Dev. (1998) [Pubmed]
  24. Cdc53p acts in concert with Cdc4p and Cdc34p to control the G1-to-S-phase transition and identifies a conserved family of proteins. Mathias, N., Johnson, S.L., Winey, M., Adams, A.E., Goetsch, L., Pringle, J.R., Byers, B., Goebl, M.G. Mol. Cell. Biol. (1996) [Pubmed]
  25. SIC1 is ubiquitinated in vitro by a pathway that requires CDC4, CDC34, and cyclin/CDK activities. Verma, R., Feldman, R.M., Deshaies, R.J. Mol. Biol. Cell (1997) [Pubmed]
  26. An essential domain within Cdc34p is required for binding to a complex containing Cdc4p and Cdc53p in Saccharomyces cerevisiae. Mathias, N., Steussy, C.N., Goebl, M.G. J. Biol. Chem. (1998) [Pubmed]
  27. CK2-dependent phosphorylation of the E2 ubiquitin conjugating enzyme UBC3B induces its interaction with beta-TrCP and enhances beta-catenin degradation. Semplici, F., Meggio, F., Pinna, L.A., Oliviero, S. Oncogene (2002) [Pubmed]
 
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