Skip to main content
NCBI home page
Protein & Cell logoLink to Protein & Cell
. 2012 Jun 21;3(6):405–409. doi: 10.1007/s13238-012-2912-x

Continued surprises in the cytochrome c biogenesis story

Elizabeth B Sawyer 1,✉, Paul D Barker 2,✉
PMCID: PMC4875485  PMID: 22723177

Abstract

Cytochromes c covalently bind their heme prosthetic groups through thioether bonds between the vinyl groups of the heme and the thiols of a CXXCH motif within the protein. In Gram-negative bacteria, this process is catalyzed by the Ccm (cytochrome c maturation) proteins, also called System I. The Ccm proteins are found in the bacterial inner membrane, but some (CcmE, CcmG, CcmH, and CcmI) also have soluble functional domains on the periplasmic face of the membrane. Elucidation of the mechanisms involved in the transport and relay of heme and the apocytochrome from the bacterial cytosol into the periplasm, and their subsequent reaction, has proved challenging due to the fact that most of the proteins involved are membrane-associated, but recent progress in understanding some key components has thrown up some surprises. In this Review, we discuss advances in our understanding of this process arising from a substrate’s point of view and from recent structural information about individual components.

Keywords: cytochrome c, heme, Ccm, post-translational modification, cytochrome b562, heme binding

Contributor Information

Elizabeth B. Sawyer, Email: beth.sawyer@cantab.net

Paul D. Barker, Email: pdb30@cam.ac.uk

References

  1. Allen J.W., Barker P.D., Ferguson S.J. A cytochrome b562 variant with a c-type cytochrome CXXCH heme-binding motif as a probe of the Escherichia coli cytochrome c maturation system. J Biol Chem. 2003;278:52075–52083. doi: 10.1074/jbc.M307196200. [DOI] [PubMed] [Google Scholar]
  2. Allen J.W., Sawyer E.B., Ginger M.L., Barker P.D., Ferguson S.J. Variant c-type cytochromes as probes of the substrate specificity of the E. coli cytochrome c maturation (Ccm) apparatus. Biochem J. 2009;419:177–184. doi: 10.1042/BJ20081999. [DOI] [PubMed] [Google Scholar]
  3. Arnesano F., Banci L., Barker P.D., Bertini I., Rosato A., Su X.C., Viezzoli M.S. Solution structure and characterization of the heme chaperone CcmE. Biochemistry. 2002;41:13587–13594. doi: 10.1021/bi026362w. [DOI] [PubMed] [Google Scholar]
  4. Barker P.D., Ferguson S.J. Still a puzzle: why is haem covalently attached in c-type cytochromes? Structure. 1999;7:R281–R290. doi: 10.1016/S0969-2126(00)88334-3. [DOI] [PubMed] [Google Scholar]
  5. Barker P.D., Ferrer J.C., Mylrajan M., Loehr T.M., Feng R., Konishi Y., Funk W.D., MacGillivray R.T., Mauk A.G. Transmutation of a heme protein. Proc Natl Acad Sci U S A. 1993;90:6542–6546. doi: 10.1073/pnas.90.14.6542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Barker P.D., Nerou E.P., Freund S.M., Fearnley I.M. Conversion of cytochrome b562 to c-type cytochromes. Biochemistry. 1995;34:15191–15203. doi: 10.1021/bi00046a027. [DOI] [PubMed] [Google Scholar]
  7. Daltrop O., Allen J.W.A., Willis A.C., Ferguson S.J. In vitro formation of a c-type cytochrome. Proc Natl Acad Sci U S A. 2002;99:7872–7876. doi: 10.1073/pnas.132259099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Daltrop O., Stevens J.M., Higham C.W., Ferguson S.J. The CcmE protein of the c-type cytochrome biogenesis system: unusual in vitro heme incorporation into apo-CcmE and transfer from holo-CcmE to apo-cytochrome. Proc Natl Acad Sci U S A. 2002;99:9703–9708. doi: 10.1073/pnas.152120699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Enggist E., Thöny-Meyer L., Güntert P., Pervushin K. NMR structure of the heme chaperone CcmE reveals a novel functional motif. Structure. 2002;10:1551–1557. doi: 10.1016/S0969-2126(02)00885-7. [DOI] [PubMed] [Google Scholar]
  10. Fee J.A., Todaro T.R., Luna E., Sanders D., Hunsicker-Wang L.M., Patel K.M., Bren K.L., Gomez-Moran E., Hill M.G., Ai J., et al. Cytochrome rc552, formed during expression of the truncated, Thermus thermophilus cytochrome c552 gene in the cytoplasm of Escherichia coli, reacts spontaneously to form protein-bound 2-formyl-4-vinyl (Spirographis) heme. Biochemistry. 2004;43:12162–12176. doi: 10.1021/bi048968l. [DOI] [PubMed] [Google Scholar]
  11. Feissner R.E., Richard-Fogal C.L., Frawley E.R., Kranz R.G. ABC transporter-mediated release of a haem chaperone allows cytochrome c biogenesis. Mol Microbiol. 2006;61:219–231. doi: 10.1111/j.1365-2958.2006.05221.x. [DOI] [PubMed] [Google Scholar]
  12. Kranz R., Lill R., Goldman B., Bonnard G., Merchant S. Molecular mechanisms of cytochrome c biogenesis: three distinct systems. Mol Microbiol. 1998;29:383–396. doi: 10.1046/j.1365-2958.1998.00869.x. [DOI] [PubMed] [Google Scholar]
  13. Kranz R.G., Richard-Fogal C., Taylor J.-S., Frawley E.R. Cytochrome c biogenesis: mechanisms for covalent modifications and trafficking of heme and for heme-iron redox control. Microbiol Mol Biol Rev. 2009;73:510–528. doi: 10.1128/MMBR.00001-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Liu X., Kim C.N., Yang J., Jemmerson R., Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996;86:147–157. doi: 10.1016/S0092-8674(00)80085-9. [DOI] [PubMed] [Google Scholar]
  15. Richard-Fogal C.L., Frawley E.R., Bonner E.R., Zhu H., San Fran cisco B., Kranz R.G. A conserved haem redox and trafficking pathway for cofactor attachment. EMBO J. 2009;28:2349–2359. doi: 10.1038/emboj.2009.189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Richard-Fogal C.L., Frawley E.R., Kranz R.G. Topology and function of CcmD in cytochrome c maturation. J Bacteriol. 2008;190:3489–3493. doi: 10.1128/JB.00146-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. San Francisco B., Bretsnyder E.C., Rodgers K.R., Kranz R.G. Heme ligand identification and redox properties of the cytochrome c synthetase, CcmF. Biochemistry. 2011;50:10974–10985. doi: 10.1021/bi201508t. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Sawyer E.B., Stephens E., Ferguson S.J., Allen J.W.A., Barker P.D. Aberrant attachment of heme to cytochrome by the Ccm system results in a cysteine persulfide linkage. J Am Chem Soc. 2010;132:4974–4975. doi: 10.1021/ja908241v. [DOI] [PubMed] [Google Scholar]
  19. Schulz H., Hennecke H., Thöny-Meyer L. Prototype of a heme chaperone essential for cytochrome c maturation. Science. 1998;281:1197–1200. doi: 10.1126/science.281.5380.1197. [DOI] [PubMed] [Google Scholar]
  20. Stevens J.M., Mavridou D.A.I., Hamer R., Kritsiligkou P., Goddard A.D., Ferguson S.J. Cytochrome c biogenesis System I. FEBS J. 2011;278:4170–4178. doi: 10.1111/j.1742-4658.2011.08376.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Thöny-Meyer L. Cytochrome c maturation: a complex pathway for a simple task? Biochem Soc Trans. 2002;30:633–638. doi: 10.1042/bst0300633. [DOI] [PubMed] [Google Scholar]
  22. Thöny-Meyer L., Fischer F., Künzler P., Ritz D., Hennecke H. Escherichia coli genes required for cytochrome c maturation. J Bacteriol. 1995;177:4321–4326. doi: 10.1128/jb.177.15.4321-4326.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Protein & Cell are provided here courtesy of Oxford University Press

RESOURCES