Cytochrome c

Cytochrome c, somatic
Three-dimensional structure of cytochrome c (green) with a heme molecule coordinating a central Iron atom (orange).
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1J3S, 3NWV, 3ZCF, 3ZOO
Identifiers
Symbols	CYCS ; CYC; HCS; THC4
External IDs	OMIM: 123970 MGI: 88578 HomoloGene: 133055 GeneCards: CYCS Gene
Gene ontology Molecular function • protein serine/threonine phosphatase activity • protein binding • heme binding • electron transporter, transferring electrons from CoQH2-cytochrome c reductase complex and cytochrome c oxidase complex activity • metal ion binding Cellular component • protein phosphatase type 2A complex • nucleus • mitochondrion • mitochondrial inner membrane • mitochondrial intermembrane space • cytosol • respiratory chain Biological process • response to reactive oxygen species • mitochondrial electron transport, ubiquinol to cytochrome c • mitochondrial electron transport, cytochrome c to oxygen • apoptotic DNA fragmentation • transcription initiation from RNA polymerase II promoter • apoptotic process • organelle organization • mitochondrion organization • activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c • gene expression • programmed cell death • dephosphorylation • respiratory electron transport chain • ATP synthesis coupled electron transport • cellular metabolic process • small molecule metabolic process • cellular respiration • intrinsic apoptotic signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	54205	13063
Ensembl	ENSG00000172115	ENSMUSG00000063694
UniProt	P99999	P62897
RefSeq (mRNA)	NM_018947	NM_007808
RefSeq (protein)	NP_061820	NP_031834
Location (UCSC)	Chr 7: 25.12 – 25.13 Mb	Chr 6: 50.56 – 50.57 Mb
PubMed search	[1]	[2]

The cytochrome complex, or cyt c is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly water soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an essential component of the electron transport chain, where it carries one electron. It is capable of undergoing oxidation and reduction, but does not bind oxygen. It transfers electrons between Complexes III (Coenzyme Q – Cyt C reductase) and IV (Cyt C oxidase). In humans, cytochrome c is encoded by the CYCS gene.

Function

Cytochrome c is a component of the electron transport chain in mitochondria. The heme group of cytochrome c accepts electrons from the bc₁ complex and transfers electrons to the complex IV. Cytochrome c is also involved in initiation of apoptosis. Upon release of cytochrome c to the cytoplasm, the protein binds apoptotic protease activating factor-1 (Apaf-1).

Cytochrome c can catalyze several reactions such as hydroxylation and aromatic oxidation, and shows peroxidase activity by oxidation of various electron donors such as 2,2-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), 2-keto-4-thiomethyl butyric acid and 4-aminoantipyrine.

Cytochrome c is involved in one form of nitrite reductase.

Species distribution

Tunafish cytochrome c crystals (~5 mm long) grown by liquid–liquid diffusion under microgravity conditions in outer space.

Cytochrome c is a highly conserved protein across the spectrum of species, found in plants, animals, and many unicellular organisms. This, along with its small size (molecular weight about 12,000 daltons), makes it useful in studies of cladistics. The cytochrome c molecule has been studied for the glimpse it gives into evolutionary biology.

Its primary structure consists of a chain of about 100 amino acids. Many higher order organisms possess a chain of 104 amino acids. The sequences of cytochrome c in humans is identical to that of chimpanzees (our closest relatives), but differs more from that of horses.

Its amino acid sequence is highly conserved in eukaryotes differing by only a few residues. In more than thirty species, 34 of the 104 amino acids are conserved; identical at that position. For example, human cytochrome oxidase reacts with wheat cytochrome c, in vitro, and this is true for all pairs of species tested. In addition the redox potential of +0.25 volts is the same in all cytochrome c molecules studied.

Classes

In 1991 R. P. Ambler recognized four classes of cytochrome c:

• Class I includes the lowspin soluble cytochrome c of mitochondria and bacteria. It has the heme-attachment site towards the N terminus of histidine and the sixth ligand provided by a methionine residue towards the C terminus.
• Class II includes the highspin cytochrome c'. It has the heme-attachment site closed to the N terminus of histidine.
• Class III comprises the low redox potential multiple heme cytochromes. The heme c groups are structurally and functionally nonequivalent and present different redox potentials in the range 0 to −400 mV.
• Class IV was originally created to hold the complex proteins that have other prosthetic groups as well as heme c.

Applications

Cytochrome c is suspected to be the functional complex in so called LLLT: Low-level laser therapy. In LLLT, red light and some near infra-red wavelengths penetrate tissue in order to increase cellular regeneration. Light of this wavelength appears capable of increasing activity of cytochrome c, thus increasing metabolic activity and freeing up more energy for the cells to repair the tissue.

Role in apoptosis

Overview of signal transduction pathways involved in apoptosis.

Cytochrome c is also an intermediate in apoptosis, a controlled form of cell death used to kill cells in the process of development or in response to infection or DNA damage.

Cytochrome c binds to cardiolipin in the inner mitochondrial membrane, thus anchoring its presence and keeping it from releasing out of the mitochondria and initiating apoptosis. While the initial attraction between cardiolipin and cytochrome c is electrostatic due to the extreme positive charge on cytochrome c, the final interaction is hydrophobic, where a hydrophobic tail from cardiolipin inserts itself into the hydrophobic portion of cytochrome c.

During the early phase of apoptosis, mitochondrial ROS production is stimulated, and cardiolipin is oxidized by a peroxidase function of the cardiolipin–cytochrome c complex. The hemoprotein is then detached from the mitochondrial inner membrane and can be extruded into the soluble cytoplasm through pores in the outer membrane.

The sustained elevation in calcium levels precedes cyt c release from the mitochondria. The release of small amounts of cyt c leads to an interaction with the IP3 receptor (IP3R) on the endoplasmic reticulum (ER), causing ER calcium release. The overall increase in calcium triggers a massive release of cyt c, which then acts in the positive feedback loop to maintain ER calcium release through the IP3Rs. This explains how the ER calcium release can reach cytotoxic levels. This release of cytochrome c in turn activates caspase 9, a cysteine protease. Caspase 9 can then go on to activate caspase 3 and caspase 7, which are responsible for destroying the cell from within.

Extramitochondrial localization

Cytochrome c is widely believed to be localized solely in the mitochondrial intermembrane space under normal physiological conditions. The release of cytochrome-c from mitochondria to the cytosol, where it activates the caspase family of proteases is believed to be primary trigger leading to the onset of apoptosis. Measuring the amount of cytochrome c leaking from mitochondria to cytosol, and out of the cell to culture medium, is a sensitive method to monitor the degree of apoptosis. However, detailed immunoelectron microscopic studies with rat tissues sections employing cytochrome c-specific antibodies provide compelling evidence that cytochrome-c under normal cellular conditions is also present at extramitochondrial locations. In pancreatic acinar cells and the anterior pituitary, strong and specific presence of cytochrome-c was detected in zymogen granules and in growth hormone granules respectively. In the pancreas, cytochrome-c was also found in condensing vacuoles and in the acinar lumen. The extramitochondrial localization of cytochrome c was shown to be specific as it was completely abolished upon adsorption of the primary antibody with the purified cytochrome c. The presence of cytochrome-c outside of mitochondria at specific location under normal physiological conditions raises important questions concerning its cellular function and translocation mechanism. Besides cytochrome c, extramitochondrial localization has also been observed for large numbers of other proteins including those encoded by mitochondrial DNA. This raises the possibility about existence of yet-unidentified specific mechanisms for protein translocation from mitochondria to other cellular destinations.

See also

• PEGylation

External links

• The Cytochrome c Protein
• Apoptosis & Caspase 3 – PMAP The Proteolysis Map-animation
• UMich Orientation of Proteins in Membranes families/superfamily-78 – Calculated orientations of cytochromes c in the lipid bilayer
• Cytochrome c at the US National Library of Medicine Medical Subject Headings (MeSH)