Cytochromes ccytochromes, or heme-containing proteins, that have heme Ccovalently attached to the peptide backbone via one or two thioether bonds. These bonds are in most cases part of a specific Cys-X-X-Cys-His binding motif, where X denotes a miscellaneous amino acid. Two thioether bonds of cysteine residues bind to the vinyl sidechains of heme, and the histidine residue coordinates one axial binding site of the heme iron. Less common binding motifs can include a single thioether linkage, a lysine or a methionine instead of the axial histidine or a CXnCH binding motif with n>2. The second axial site of the iron can be coordinated by amino acids of the protein, substrate molecules or water. Cytochromes c possess a wide range of properties and function as electron transfer proteins or catalysechemical reactions involving redox processes. A prominent member of this family is mitochondrial cytochrome c.
Classification
Cytochrome c proteins can be divided in four classes based on their size, number of heme groups and reduction potentials:
Class I
Small soluble cytochrome c proteins with a molecular weight of 8-12 kDa and a single heme group belong to class I. It includes the low-spin soluble cytC of mitochondria and bacteria, with the heme-attachment site located towards the N-terminus, and the sixth ligand provided by a methionine residue about 40 residues further on towards the C-terminus. The typical class I fold contains five α-helices. On the basis of sequence similarity, class I cytC were further subdivided into five classes, IA to IE. Class IB includes the eukaryotic mitochondrial cyt c and prokaryotic 'short' cyt c2 exemplified by Rhodopila globiformis cyt c2; class IA includes 'long' cyt c2, such as Rhodospirillum rubrum cyt c2 and Aquaspirillum itersonii cyt c550, which have several extra loops by comparison with class IB cyt c. The linked InterPro entry represents mono-haem cytochrome c proteins, such as cytochromes c, c1, c2, c5, c555, c550-c553, c556, c6 and cbb3. Dihaem cytochrome c are proteins with a class I cluster and a unique cluster.
Subclasses
Cytochrome c, class IA/IB
Cytochrome c, class IC
Cytochrome c, class ID
Cytochrome c, class IE
Class II
The heme group in class II cytochrome c proteins is attached to a C-terminal binding motif. The structural fold of class II c-type cytochromes contains a four α-helix bundle with the covalently attached heme group at its core. Representatives of class II are the high-spin cytochrome c' and a number of low-spin cytochromes c, e.g. cyt c556. The cyt c' are capable of binding such ligands as CO, NO or CN−, albeit with rate and equilibrium constants 100 to 1,000,000-fold smaller than other high-spin hemeproteins. This, coupled with its relatively low redox potential, makes it unlikely that cyt c' is a terminal oxidase. Thus cyt c' probably functions as an electron transfer protein. The 3D structures of a number of cyt c' have been determined which show that the proteins usually exist as a dimer. The Chromatium vinosum cyt c' exhibits dimer dissociation upon ligand binding.
Class III
Proteins containing multiple covalently attached heme groups with low redox potential are included in class III. The heme C groups, all bis-histidinyl coordinated, are structurally and functionally nonequivalent and present different redox potentials in the range 0 to -400 mV. Members of this class are e.g. cytochrome c7, cytochrome c3, and high-molecular-weight cytochrome c, cointaining 16 heme groups with only 30-40 residues per heme group. The 3D structures of a number of cyt c3 proteins have been determined. The proteins consist of 4-5 α-helices and 2 β-sheets wrapped around a compact core of four non-parallel hemes, which present a relatively high degree of exposure to the solvent. The overall protein architecture, heme plane orientations and iron-iron distances are highly conserved. An example is the Photosynthetic reaction centre of Rhodopseudomonas viridis that contains a tetraheme cytochrome c subunit.
Class IV
According to Ambler, Cytochrome c proteins containing other prosthetic groups besides heme C, such as flavocytochromes c and cytochromes cd1 belong to class IV. As this grouping is more related to how the heme group is used instead of what the domains themselves look like, proteins placed in this group tend to be scattered in others in bioinformatic groupings.
Also called cytochrome c maturation and found in proteobacteria, plant mitochondria, some protozoal mitochondria, deinococci and archaea. Ccm comprises at least eight membrane proteins that are needed for electron transfer to the heme group, apo-cytochrome handling and attachment of the heme to the apo-cytochrome. An ABC-transporter-like complex formed by CcmA2BCD attaches a heme group to CcmE with the use of ATP. CcmE transports the heme to CcmF where the attachment to the apo-cytochrome occurs. Transport of the apoprotein from the cytoplasm to the periplasm happens via the Sec translocation system. CcmH is used by the system to recognize the apo-cytochrome and direct it to CcmF.
System II
Cytochromes c in chloroplasts, Gram-positive bacteria, cyanobacteria and some proteobacteria are produced by the cytochrome c synthesis system. It is composed of two membrane proteins CcsB and CcsA. The CcsBA protein complex was suggested to act as a heme transporter during the attachment process. In some organisms such as Helicobacter hepaticus both proteins are found as a fused single protein. Apoprotein transport occurs via the Sec translocon as well.
System III
, vertebrate and invertebrate mitochondria produce cytochrome c proteins with a single enzyme called HCCS or cytochrome c heme lyase. The protein is attached to the inner membrane of the intermembrane space. In some organisms, such as Saccharomyces cerevisiae, cytochrome c and cytochrome c1 are synthesized by separate heme lyases, CCHL and CC1HL respectively. In Homo sapiens a single HCCS is used for the biosynthesis of both cytochrome c proteins.
System IV
Four membrane proteins are necessary for the attachment of a heme in cytochrome b6. A major difference to systems I-III is that the heme attachment occurs at the opposite side of the lipid bilayer compared to the other systems.
