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Gene Review

ccdA  -  CcdA

Escherichia coli B171

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Ambiguity problem


  • CcdA (control of cell death) of the E. coli F-plasmid is [1] a 72 aa protein. It inactivates the toxic CcdB and so creates an immunity in the cell to the toxic effects of CcdB. It is used commercially in a number of plasmid selection systems, notably the Invitrogen Gateway® system.
  • The CcdA (cytochrome C deficient) of B. subtilis [2] is a 235 aa protein. It is a thiol-reductase and a homologue of the E. coli DsbD protein [3]. If you run the two proteins through a blastP search there are no significant similarities found between the CcdA of Bacillus and the CcdA of the E. coli F-plasmid. The CcdA protein of R. capsulatus [4] is also a thiol reductase and related to the CcdA of B. subtilus and not the E. coli F-plasmid CcdA.

Disease relevance of ccdA

  • The ccd mechanism specified by the ccdA and ccdB genes of the mini-F plasmid determines fate of plasmid-free segregants in Escherichia coli (Jaffé et al., J. Bacteriol. 163:841-849, 1985) [5].
  • Identification and characterization of the ccdA gene, required for cytochrome c synthesis in Bacillus subtilis [2].
  • Both induction of prophage and inhibition of cell division are suppressed by the simultaneous presence of a replication proficient plasmid carrying the ccdA gene [6].
  • We used reciprocal heterologous complementation assays between E.coli and Rhodobacter capsulatus to show that, despite their differences in size and structure, DsbD and CcdA are functional homologs [7].
  • This study demonstrated for the first time that CcdA homologues are also required for cyt c biogenesis in some gram-negative bacteria such as R. capsulatus [8].

High impact information on ccdA

  • Most bacterial species do not have DsbD, but instead their genomes encode a much smaller protein, CcdA, which resembles the central hydrophobic domain of DsbD [7].
  • The sequence was fused at the C-terminal end of the CcdB and CcdA proteins encoded by plasmid F [9].
  • Experimental results suggest that reduction of the copy number of plasmids carrying the ccd region causes an inhibition of cell division and that the ccd region can be dissected into two functional regions; one (ccdB) inhibits cell division and the other (ccdA) releases the inhibition [10].
  • An analysis of the available complete genomes provides further evidence for this proposition in other bacteria where DsbD/CcdA, Trx, MsrA, and MsrB gene homologs are all located in a gene cluster with a common transcriptional direction [11].
  • PinA inhibited cleavage of the 72-amino acid protein, CcdA, degradation of which requires ATP hydrolysis, but did not inhibit cleavage of the carboxyl-terminal 41-amino acid fragment of CcdA, degradation of which does not require ATP hydrolysis [12].

Chemical compound and disease context of ccdA

  • Both these cysteine residues, plus other transmembrane helix residues, notably prolines and glycines, are also conserved in a group of membrane proteins, related to Bacillus subtilis CcdA, which lack the N- and C-terminal hydrophilic domains of the DipZ proteins [13].

Biological context of ccdA

  • The results showed that the H (ccdA), G (ccdB) and D genes, together with a promoter, comprise an operon [14].
  • Subsequent footprinting of the binding sites showed protection over about a 113-base-pair region encompassing the putative promoter-operator and the beginning of the ccdA gene [15].
  • CcdA, the antidote protein of the ccd post-segregational killing system carried by the F plasmid, was degraded in vitro by purified Lon protease from Escherichia coli [16].
  • Lon cleaved CcdA primarily between aliphatic and hydrophilic residues, and CcdA41 was cleaved at the same peptide bonds, indicating that ATP hydrolysis does not affect cleavage specificity [16].
  • Mutagenesis of these cysteines showed that both are required for the function of CcdA in cyt c biogenesis [8].

Anatomical context of ccdA


Associations of ccdA with chemical compounds

  • The deduced topology revealed that the two conserved cysteine residues of CcdA are, as predicted, membrane embedded [8].

Other interactions of ccdA


Analytical, diagnostic and therapeutic context of ccdA

  • Crystallization of the C-terminal domain of the addiction antidote CcdA in complex with its toxin CcdB [17].




  1. Lon-dependent proteolysis of CcdA is the key control for activation of CcdB in plasmid-free segregant bacteria. Van Melderen, L., Bernard, P., Couturier, M. Mol. Microbiol. (1994) [Pubmed]
  2. Identification and characterization of the ccdA gene, required for cytochrome c synthesis in Bacillus subtilis. Schiött, T., von Wachenfeldt, C., Hederstedt, L. J. Bacteriol. (1997) [Pubmed]
  3. Identification and characterization of a new disulfide isomerase-like protein (DsbD) in Escherichia coli. Missiakas, D., Schwager, F., Raina, S. EMBO. J. (1995) [Pubmed]
  4. The dithiol:disulfide oxidoreductases DsbA and DsbB of Rhodobacter capsulatus are not directly involved in cytochrome c biogenesis, but their inactivation restores the cytochrome c biogenesis defect of CcdA-null mutants. Deshmukh, M., Turkarslan, S., Astor, D., Valkova-Valchanova, M., Daldal, F. J. Bacteriol. (2003) [Pubmed]
  5. F plasmid ccd mechanism in Escherichia coli. Hiraga, S., Jaffé, A., Ogura, T., Mori, H., Takahashi, H. J. Bacteriol. (1986) [Pubmed]
  6. Prophage lambda induction caused by mini-F plasmid genes. Mori, H., Ogura, T., Hiraga, S. Mol. Gen. Genet. (1984) [Pubmed]
  7. Evolutionary domain fusion expanded the substrate specificity of the transmembrane electron transporter DsbD. Katzen, F., Deshmukh, M., Daldal, F., Beckwith, J. EMBO J. (2002) [Pubmed]
  8. Novel Rhodobacter capsulatus genes required for the biogenesis of various c-type cytochromes. Deshmukh, M., Brasseur, G., Daldal, F. Mol. Microbiol. (2000) [Pubmed]
  9. Bacteriophage Mu repressor as a target for the Escherichia coli ATP-dependent Clp Protease. Laachouch, J.E., Desmet, L., Geuskens, V., Grimaud, R., Toussaint, A. EMBO J. (1996) [Pubmed]
  10. Mini-F plasmid genes that couple host cell division to plasmid proliferation. Ogura, T., Hiraga, S. Proc. Natl. Acad. Sci. U.S.A. (1983) [Pubmed]
  11. The Thioredoxin Domain of Neisseria gonorrhoeae PilB Can Use Electrons from DsbD to Reduce Downstream Methionine Sulfoxide Reductases. Brot, N., Collet, J.F., Johnson, L.C., J??nsson, T.J., Weissbach, H., Lowther, W.T. J. Biol. Chem. (2006) [Pubmed]
  12. PinA inhibits ATP hydrolysis and energy-dependent protein degradation by Lon protease. Hilliard, J.J., Simon, L.D., Van Melderen, L., Maurizi, M.R. J. Biol. Chem. (1998) [Pubmed]
  13. Disruption of the Pseudomonas aeruginosa dipZ gene, encoding a putative protein-disulfide reductase, leads to partial pleiotropic deficiency in c-type cytochrome biogenesis. Page, M.D., Saunders, N.F., Ferguson, S.J. Microbiology (Reading, Engl.) (1997) [Pubmed]
  14. Autoregulation of the ccd operon in the F plasmid. de Feyter, R., Wallace, C., Lane, D. Mol. Gen. Genet. (1989) [Pubmed]
  15. Control of the ccd operon in plasmid F. Tam, J.E., Kline, B.C. J. Bacteriol. (1989) [Pubmed]
  16. ATP-dependent degradation of CcdA by Lon protease. Effects of secondary structure and heterologous subunit interactions. Van Melderen, L., Thi, M.H., Lecchi, P., Gottesman, S., Couturier, M., Maurizi, M.R. J. Biol. Chem. (1996) [Pubmed]
  17. Crystallization of the C-terminal domain of the addiction antidote CcdA in complex with its toxin CcdB. Buts, L., De Jonge, N., Loris, R., Wyns, L., Dao-Thi, M.H. Acta Crystallograph. Sect. F Struct. Biol. Cryst. Commun. (2005) [Pubmed]
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