Cytochromes ''c'' (cyt ''c'', c-type cytochromes)

cytochromes Cytochromes are redox-active proteins containing a heme, with a central Fe atom at its core, as a cofactor. They are involved in electron transport chain and redox catalysis. They are classified according to the type of heme and its mode of bi ...

, or heme-containing

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

s, that have heme C

covalently A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atom ...

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 (CXXCH) binding motif, where X denotes a miscellaneous

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

. 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 Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in ...

. Less common binding motifs can include a single thioether linkage, a lysine or a methionine instead of the axial histidine or a CX_nCH 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 Water (chemical formula ) is an inorganic, transparent, tasteless, odorless, and nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living organisms (in which it acts as ...

. Cytochromes ''c'' possess a wide range of properties and function as electron transfer proteins or catalyse chemical 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 A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bio ...

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 The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

, and the sixth ligand provided by a

methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ...

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 Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...

mitochondrial cyt ''c'' and prokaryotic 'short' cyt ''c''₂ exemplified by '' Rhodopila globiformis'' cyt ''c''₂; class IA includes 'long' cyt ''c''₂, such as '' Rhodospirillum rubrum'' cyt ''c''₂ and '' Aquaspirillum itersonii'' cyt ''c''₅₅₀, which have several extra loops by comparison with class IB cyt ''c''. The linked InterPro entry represents mono-haem cytochrome c proteins (excluding class II and f-type cytochromes), 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 The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ...

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 ''c''₅₅₆. The cyt ''c''' are capable of binding such

ligands In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...

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 Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or ...

potential, makes it unlikely that cyt ''c''' is a terminal oxidase. Thus cyt ''c''' probably functions as an

electron transfer protein The electron ( or ) is a subatomic particle with a negative one elementary electric charge. Electrons belong to the first generation of the lepton particle family, and are generally thought to be elementary particles because they have no ...

. The 3D structures of a number of cyt ''c''' have been determined which show that the proteins usually exist as a

dimer Dimer may refer to: * Dimer (chemistry), a chemical structure formed from two similar sub-units ** Protein dimer, a protein quaternary structure ** d-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * Julius Dimer ( ...

. The ''Chromatium vinosum'' cyt ''c''' exhibits

dissociation upon

ligand binding In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mo ...

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

potentials in the range 0 to -400 mV. Members of this class are e.g. cytochrome ''c''₇ (triheme), cytochrome ''c''₃ (tetraheme), and high-molecular-weight cytochrome ''c'' (Hmc), containing 16 heme groups with only 30-40 residues per heme group. The 3D

structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such a ...

s of a number of cyt ''c''₃

s have been determined. The proteins consist of 4-5 α-helices and 2

β-sheets The beta sheet, (β-sheet) (also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gen ...

wrapped around a compact core of four non-parallel hemes, which present a relatively high degree of exposure to the

solvent A solvent (s) (from the Latin '' solvō'', "loosen, untie, solve") is a substance that dissolves a solute, resulting in a solution. A solvent is usually a liquid but can also be a solid, a gas, or a supercritical fluid. Water is a solvent for ...

. The overall protein architecture, heme plane orientations and iron-iron distances are highly conserved. An example is the Photosynthetic reaction centre of ''

Rhodopseudomonas ''Rhodopseudomonas'' is a genus of bacteria from the family Nitrobacteraceae. Phylogeny The currently accepted taxonomy is based on the List of Prokaryotic names with Standing in Nomenclature List of Prokaryotic names with Standing in Nome ...

viridis'' that contains a tetraheme cytochrome ''c'' subunit.

Class IV

According to Ambler (1991), Cytochrome ''c'' proteins containing other prosthetic groups besides heme C, such as flavocytochromes ''c'' (sulfide dehydrogenase) and cytochromes ''cd₁'' (nitrite reductase) 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.

Biogenesis

The attachment of the heme group is physically separated from the

protein biosynthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critical ...

. Proteins are synthesized within the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...

and

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...

, while the maturation of cytochromes ''c'' occurs in the periplasm of prokaryots, the intermembrane space of mitochondria or the stroma of

chloroplast A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant and algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, and stores it i ...

s. Several

biochemical pathways In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...

have been discovered that differ depending on organism.

System I

Also called cytochrome ''c'' maturation (ccm) and found in

Pseudomonadota Pseudomonadota (synonym Proteobacteria) is a major phylum of Gram-negative bacteria. The renaming of phyla in 2021 remains controversial among microbiologists, many of whom continue to use the earlier names of long standing in the literature. Th ...

, plant mitochondria, some

protozoa Protozoa (singular: protozoan or protozoon; alternative plural: protozoans) are a group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic tissues and debris. Histo ...

l mitochondria, deinococci, and

archaea Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaeba ...

. Ccm comprises at least eight

membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...

s (CcmABCDEFGH) 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

s, Gram-positive bacteria,

cyanobacteria Cyanobacteria (), also known as Cyanophyta, are a phylum of gram-negative bacteria that obtain energy via photosynthesis. The name ''cyanobacteria'' refers to their color (), which similarly forms the basis of cyanobacteria's common name, bl ...

, and some Pseudomonadota are produced by the cytochrome ''c'' synthesis (ccs) 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 ''Helicobacter hepaticus'' is a bacterium in the Helicobacteraceae family, Campylobacterales order. It has a spiral shape and bipolar, single, sheathed flagellum, and was first isolated from the livers of mice with active, chronic hepatitis. Th ...

'' both proteins are found as a fused single protein. Apoprotein transport occurs via the Sec translocon as well.

System III

Fungal,

vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with ...

and

invertebrate Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chorda ...

mitochondria produce cytochrome ''c'' proteins with a single enzyme called HCCS ( holocytochrome c synthase) or cytochrome ''c'' heme lyase (CCHL). The protein is attached to the inner membrane of the intermembrane space. In some organisms, such as ''

Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have b ...

'', cytochrome ''c'' and cytochrome ''c''₁ are synthesized by separate heme lyases, CCHL and CC1HL respectively. In ''

Homo sapiens Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture ...

'' 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 ''b''6. 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.

Human proteins containing this domain

CYCS; CYC1

References

{{InterPro content, IPR020942 Protein domains Peripheral membrane proteins