Interaction of HoloCcmE with CcmF in Heme Trafficking and Cytochrome c Biosynthesis
Open accessAbstract
The periplasmic heme chaperone holoCcmE is essential for heme trafficking in the cytochrome c biosynthetic pathway in many bacteria, archaea, and plant mitochondria. This pathway, called system I, involves two steps: (i) formation and release of holoCcmE (by the ABC-transporter complex CcmABCD) and (ii) delivery of the heme in holoCcmE to the putative cytochrome c heme lyase complex, CcmFH. CcmFH is believed to facilitate the final covalent attachment of heme (from holoCcmE) to the apocytochrome c. Although most models for system I propose that holoCcmE delivers heme directly to CcmF, no interaction between holoCcmE and CcmF has been demonstrated. Here, a complex between holoCcmE and CcmF is “trapped”, purified, and characterized. HoloCcmE must be released from the ABC-transporter complex CcmABCD to interact with CcmF, and the holo-form of CcmE interacts with CcmF at levels at least 20-fold higher than apoCcmE. Two conserved histidines (here termed P-His1 and P-His2) in separate periplasmic loops in CcmF are required for interaction with holoCcmE, and evidence that P-His1 and P-His2 function as heme-binding ligands is presented. These results show that heme in holoCcmE is essential for complex formation with CcmF and that the heme of holoCcmE is coordinated by P-His1 and P-His2 within the WWD domain of CcmF. These features are strikingly similar to formation of the CcmC:heme:CcmE ternary complex [Richard-Fogal C, Kranz RG. The CcmC:heme:CcmE complex in heme trafficking and cytochrome c biosynthesis. J Mol Biol 2010;401:350–62] and suggest common mechanistic and structural aspects.
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CcmE shuttles the heme from module 1 to module 2, composed of CcmFGH, where the heme is delivered to CcmF.
“CcmE then shuttles the heme from module 1 to module 2, composed of CcmFGH, where the heme is delivered to CcmF44.”
From AF2Complex predicts direct physical interactions in multimeric proteins with deep learning (2022) · cites this paper as [44]
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Cites
Simultaneous determination of hemes a, b, and c from pyridine hemochrome spectra
Berry, E. A., & Trumpower, B. L. (1987) · Analytical Biochemistry · doi:10.1016/0003-2697(87)90643-9 · Cited by 918 · see citing works
Kranz, R. G., Richard-Fogal, C., Taylor, J.-S., & Frawley, E. R. (2009) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00001-09 · Cited by 275 · see citing works
Self-citationMmicular mechanisms of cytochrome c biogenesis: three distinct systems
Kranz, R. G., Lill, R., Goldman, B. S., Bonnard, G., & Merchant, S. (1998) · Molecular Microbiology · doi:10.1046/j.1365-2958.1998.00869.x · Cited by 257 · see citing works
Self-citationCytochrome c biogenesis: the Ccm system
Sanders, C., Turkarslan, S., Lee, D.-W., & Daldal, F. (2010) · Trends in Microbiology · doi:10.1016/j.tim.2010.03.006 · Cited by 197 · see citing works
Bacterial cytochromes c biogenesis.Preprint
Beckman, D. L., Trawick, D. R., & Kranz, R. G. (1992) · Genes & Development · doi:10.1101/gad.6.2.268 · Cited by 181 · see citing works
Self-citationBarrick, D. (1994) · Biochemistry · doi:10.1021/bi00187a023 · Cited by 145 · see citing works
Schulz, H., Fabianek, R. A., Pellicioli, E. C., Hennecke, H., & Thöny‐Meyer, L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.11.6462 · Cited by 128 · see citing works
Beckman, D. L., & Kranz, R. G. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.6.2179 · Cited by 108 · see citing works
Self-citationTransmembrane heme delivery systems
Goldman, B. S., Beck, D. L., Monika, E. M., & Kranz, R. G. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.9.5003 · Cited by 106 · see citing works
Self-citationNicholson, D. W., & Neupert, W. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.12.4340 · Cited by 99 · see citing works
A Bacterial Cytochrome c Heme Lyase
Ren, Q., Ahuja, U., & Thöny‐Meyer, L. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110979200 · Cited by 96 · see citing works
Meyer, E. H., Giegé, P., Gelhaye, É., Rayapuram, N., Ahuja, U., Thöny‐Meyer, L., Grienenberger, J. M., & Bonnard, G. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0503473102 · Cited by 91 · see citing works
Transmutation of a heme protein.
Barker, P. D., Ferrer, J. C., Mylrajan, M., Loehr, T. M., Feng, R., Konishi, Y., Funk, W. D., MacGillivray, R. T. A., & Mauk, A. G. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.14.6542 · Cited by 90 · see citing works
Feissner, R. E., Richard‐Fogal, C. L., Frawley, E. R., Loughman, J. A., Earley, K. W., & Kranz, R. G. (2006) · Molecular Microbiology · doi:10.1111/j.1365-2958.2006.05132.x · Cited by 88 · see citing works
Self-citationChemiluminescent-based methods to detect subpicomole levels of c-type cytochromes
Feissner, R. E., Xiang, Y., & Kranz, R. G. (2003) · Analytical Biochemistry · doi:10.1016/s0003-2697(02)00658-9 · Cited by 86 · see citing works
Self-citationABC transporter‐mediated release of a haem chaperone allows cytochrome <i>c</i> biogenesis
Feissner, R. E., Richard‐Fogal, C. L., Frawley, E. R., & Kranz, R. G. (2006) · Molecular Microbiology · doi:10.1111/j.1365-2958.2006.05221.x · Cited by 85 · see citing works
Self-citationBiochemical requirements for the maturation of mitochondrial c-type cytochromes
Hamel, P. P., Corvest, V., Giegé, P., & Bonnard, G. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2008.06.017 · Cited by 79 · see citing works
CcsBA is a cytochrome c synthetase that also functions in heme transport
Frawley, E. R., & Kranz, R. G. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903132106 · Cited by 77 · see citing works
Self-citationMonika, E. M., Goldman, B. S., Beckman, D. L., & Kranz, R. G. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1997.1227 · Cited by 77 · see citing works
Self-citationGoldman, B. S., Beckman, D. L., Bali, A., Monika, E. M., Gabbert, K. K., & Kranz, R. G. (1997) · Journal of Molecular Biology · doi:10.1006/jmbi.1997.0992 · Cited by 75 · see citing works
Self-citationHamel, P. P., Dreyfuss, B. W., Xie, Z., Gabilly, S. T., & Merchant, S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m208651200 · Cited by 70 · see citing works
A conserved haem redox and trafficking pathway for cofactor attachment
Richard‐Fogal, C. L., Frawley, E. R., Bonner, E. R., Zhu, H., Francisco, B. S., & Kranz, R. G. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.189 · Cited by 66 · see citing works
Self-citationMavridou, D. A. I., Ferguson, S. J., & Stevens, J. M. (2013) · IUBMB Life · doi:10.1002/iub.1123 · Cited by 66 · see citing works
Rayapuram, N., Hagenmuller, J., Grienenberger, J. M., Bonnard, G., & Giegé, P. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m802621200 · Cited by 61 · see citing works
The Interaction of Covalently Bound Heme with the Cytochrome c Maturation Protein CcmE
Uchida, T., Stevens, J. M., Daltrop, O., Harvat, E. M., Lin, H., Ferguson, S. J., & Kitagawa, T. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408963200 · Cited by 61 · see citing works
Unusual Heme−Histidine Bond in the Active Site of a Chaperone
Lee, D., Pervushin, K. V., Bischof, D., Braun, M., & Thöny‐Meyer, L. (2005) · Journal of the American Chemical Society · doi:10.1021/ja044658e · Cited by 57 · see citing works
Christensen, O., Harvat, E. M., Thöny‐Meyer, L., Ferguson, S. J., & Stevens, J. M. (2007) · FEBS Journal · doi:10.1111/j.1742-4658.2007.05769.x · Cited by 55 · see citing works
The CcmC:Heme:CcmE Complex in Heme Trafficking and Cytochrome c Biosynthesis
Richard-Fogal, C., & Kranz, R. G. (2010) · Journal of Molecular Biology · doi:10.1016/j.jmb.2010.06.041 · Cited by 53 · see citing works
Self-citationSanders, C., Turkarslan, S., Lee, D., Önder, Ö., Kranz, R. G., & Daldal, F. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m805413200 · Cited by 49 · see citing works
Self-citationLee, J., Harvat, E. M., Stevens, J. M., Ferguson, S. J., & Saier, M. H. (2007) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2007.04.022 · Cited by 48 · see citing works
Richard‐Fogal, C. L., Frawley, E. R., Feissner, R. E., & Kranz, R. G. (2006) · Journal of Bacteriology · doi:10.1128/jb.01388-06 · Cited by 45 · see citing works
Self-citationTurkarslan, S., Sanders, C., Ekici, S., & Daldal, F. (2008) · Molecular Microbiology · doi:10.1111/j.1365-2958.2008.06441.x · Cited by 42 · see citing works
Stevens, J. M., Daltrop, O., Higham, C. W., & Ferguson, S. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212925200 · Cited by 39 · see citing works
A Strategic Protein in Cytochrome c Maturation
Matteo, A. D., Gianni, S., Schininà, M. E., Giorgi, A., Fabio Altieri, F., Calosci, N., Brunori, M., & Travaglini‐Allocatelli, C. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702702200 · Cited by 37 · see citing works
Setterdahl, A. T., Goldman, B. S., Hirasawa, M., Jacquot, P., Smith, A. J., Kranz, R. G., & Knaff, D. B. (2000) · Biochemistry · doi:10.1021/bi000663t · Cited by 35 · see citing works
Self-citationProbing the Heme-Binding Site of the Cytochrome c Maturation Protein CcmE
Harvat, E. M., Redfield, C., Stevens, J. M., & Ferguson, S. J. (2009) · Biochemistry · doi:10.1021/bi801609a · Cited by 33 · see citing works
Heme Ligand Identification and Redox Properties of the Cytochrome c Synthetase, CcmF
Francisco, B. S., Bretsnyder, E. C., Rodgers, K. R., & Kranz, R. G. (2011) · Biochemistry · doi:10.1021/bi201508t · Cited by 31 · see citing works
Self-citationOuyang, N., Gao, Y., Hu, H., & Xia, Z. (2006) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.21184 · Cited by 29 · see citing works
Veríssimo, A. F., Yang, H., Wu, X., Sanders, C., & Daldal, F. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.277764 · Cited by 26 · see citing works
Matteo, A. D., Calosci, N., Gianni, S., Jemth, P., Brunori, M., & Travaglini‐Allocatelli, C. (2010) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.22733 · Cited by 22 · see citing works
The Heme Chaperone ApoCcmE Forms a Ternary Complex with CcmI and Apocytochrome c
Veríssimo, A. F., Mohtar, M. A., & Daldal, F. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.440024 · Cited by 14 · see citing works
Silvio, E. D., Matteo, A. D., Malatesta, F., & Travaglini‐Allocatelli, C. (2013) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2013.04.027 · Cited by 14 · see citing works
Continued surprises in the cytochrome c biogenesis story
Sawyer, E. B., & Barker, P. D. (2012) · Protein & Cell · doi:10.1007/s13238-012-2912-x · Cited by 13 · see citing works
Biochemical properties and catalytic domain structure of the CcmH protein from Escherichia coli
Zheng, X., Hong, J., Li, H., Lin, D., & Hu, H. (2012) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2012.06.017 · Cited by 12 · see citing works
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- Authors
- San Francisco, B., & Kranz, R. G.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Kranz, Robert G.
- ORCID
- Kranz, Robert G.
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 426
- Issue
- 3
- Pages
- 570-585
- ISSN
- 0022-2836 (ISSN-L)
- PMC
- PMC3943652
- OpenAlex
- W1987459562
- Cited by
- 24
- References
- 44
- Citations by year
- 2026: 2 · 2025: 3 · 2023: 3 · 2022: 1 · 2021: 4 · 2018: 2 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 4
- FWCI
- 0.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01 GM47909)
- Topics
- Physical Sciences › Energy › Renewable Energy, Sustainability and the Environment › Metalloenzymes and iron-sulfur proteins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- heme trafficking, protein-protein interaction, archaea
- MeSH terms
- Amino Acid Sequence, Bacterial Outer Membrane Proteins, Escherichia coli, Genetic Complementation Test, Heme, Hemeproteins, Imidazoles, Molecular Sequence Data, Plasmids, Spectrophotometry, Ultraviolet, Holoenzymes, Protein Transport, Escherichia coli Proteins, Cytochromes c
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