Continued surprises in the cytochrome c biogenesis story

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

References

[1] Allen, J.W., Barker, P.D., and Ferguson, S.J. (2003). 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 278, 52075-52083 .10.1074/jbc.M307196200
[2] Allen, J.W., Sawyer, E.B., Ginger, M.L., Barker, P.D., and Ferguson, S.J. (2009). Variant c-type cytochromes as probes of the substrate specificity of the E. coli cytochrome c maturation (Ccm) apparatus. Biochem J 419, 177-184 , 2, 184.
[3] Arnesano, F., Banci, L., Barker, P.D., Bertini, I., Rosato, A., Su, X.C., and Viezzoli, M.S. (2002). Solution structure and characterization of the heme chaperone CcmE. Biochemistry 41, 13587-13594 .10.1021/bi026362w
[4] Barker, P.D., and Ferguson, S.J. (1999). Still a puzzle: why is haem covalently attached in c-type cytochromes? Structure 7, R281-R290 .10.1016/S0969-2126(00)88334-3
[5] Barker, P.D., Ferrer, J.C., Mylrajan, M., Loehr, T.M., Feng, R., Konishi, Y., Funk, W.D., MacGillivray, R.T., and Mauk, A.G. (1993). Transmutation of a heme protein. Proc Natl Acad Sci U S A 90, 6542-6546 .10.1073/pnas.90.14.6542
[6] Barker, P.D., Nerou, E.P., Freund, S.M., and Fearnley, I.M. (1995). Conversion of cytochrome b₅₆₂ to c-type cytochromes. Biochemistry 34, 15191-15203 .10.1021/bi00046a027
[7] Daltrop, O., Allen, J.W.A., Willis, A.C., and Ferguson, S.J. (2002a). In vitro formation of a c-type cytochrome. Proc Natl Acad Sci U S A 99, 7872-7876 .10.1073/pnas.132259099
[8] Daltrop, O., Stevens, J.M., Higham, C.W., and Ferguson, S.J. (2002b). 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 99, 9703-9708 .10.1073/pnas.152120699
[9] Enggist, E., Th?ny-Meyer, L., Güntert, P., and Pervushin, K. (2002). NMR structure of the heme chaperone CcmE reveals a novel functional motif. Structure 10, 1551-1557 .10.1016/S0969-2126(02)00885-7
[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., . (2004). 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 43, 12162-12176 .10.1021/bi048968l
[11] Feissner, R.E., Richard-Fogal, C.L., Frawley, E.R., and Kranz, R.G. (2006). ABC transporter-mediated release of a haem chaperone allows cytochrome c biogenesis. Mol Microbiol 61, 219-231 .10.1111/j.1365-2958.2006.05221.x
[12] Kranz, R., Lill, R., Goldman, B., Bonnard, G., and Merchant, S. (1998). Molecular mechanisms of cytochrome c biogenesis: three distinct systems. Mol Microbiol 29, 383-396 .10.1046/j.1365-2958.1998.00869.x
[13] Kranz, R.G., Richard-Fogal, C., Taylor, J.-S., and Frawley, E.R. (2009). Cytochrome c biogenesis: mechanisms for covalent modifications and trafficking of heme and for heme-iron redox control. Microbiol Mol Biol Rev 73, 510-528 .10.1128/MMBR.00001-09
[14] Liu, X., Kim, C.N., Yang, J., Jemmerson, R., and Wang, X. (1996). Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86, 147-157 .10.1016/S0092-8674(00)80085-9
[15] Richard-Fogal, C.L., Frawley, E.R., Bonner, E.R., Zhu, H., San Francisco, B., and Kranz, R.G. (2009). A conserved haem redox and trafficking pathway for cofactor attachment. EMBO J 28, 2349-2359 .10.1038/emboj.2009.189
[16] Richard-Fogal, C.L., Frawley, E.R., and Kranz, R.G. (2008). Topology and function of CcmD in cytochrome c maturation. J Bacteriol 190, 3489-3493 .10.1128/JB.00146-08
[17] San Francisco, B., Bretsnyder, E.C., Rodgers, K.R., and Kranz, R.G. (2011). Heme ligand identification and redox properties of the cytochrome c synthetase, CcmF. Biochemistry 50, 10974-10985 .10.1021/bi201508t
[18] Sawyer, E.B., Stephens, E., Ferguson, S.J., Allen, J.W.A., and Barker, P.D. (2010). Aberrant attachment of heme to cytochrome by the Ccm system results in a cysteine persulfide linkage. J Am Chem Soc 132, 4974-4975 .10.1021/ja908241v
[19] Schulz, H., Hennecke, H., and Th?ny-Meyer, L. (1998). Prototype of a heme chaperone essential for cytochrome c maturation. Science 281, 1197-1200 .10.1126/science.281.5380.1197
[20] Stevens, J.M., Mavridou, D.A.I., Hamer, R., Kritsiligkou, P., Goddard, A.D., and Ferguson, S.J. (2011). Cytochrome c biogenesis System I. FEBS J 278, 4170-4178 .10.1111/j.1742-4658.2011.08376.x
[21] Th?ny-Meyer, L. (2002). Cytochrome c maturation: a complex pathway for a simple task? Biochem Soc Trans 30, 633-638 .10.1042/BST0300633
[22] Th?ny-Meyer, L., Fischer, F., Künzler, P., Ritz, D., and Hennecke, H. (1995). Escherichia coli genes required for cytochrome c maturation. J Bacteriol 177, 4321-4326 .