Biology:Cytochrome c

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example
Heme prosthetic group of cytochrome c, consisting of a rigid porphyrin ring coordinated with an iron atom.

The cytochrome complex, or cyt c, is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion where it plays a critical role in cellular respiration. It transfers electrons between Complexes III (Coenzyme Q – Cyt c reductase) and IV (Cyt c oxidase). Cytochrome c is highly water-soluble, unlike other cytochromes. It is capable of undergoing oxidation and reduction as its iron atom converts between the ferrous and ferric forms, but does not bind oxygen. It also plays a major role in cell apoptosis. In humans, cytochrome c is encoded by the CYCS gene.[1][2]

Species distribution

Cytochrome c is a highly conserved protein across the spectrum of eukaryotic species, found in plants, animals, fungi, and many unicellular organisms. This, along with its small size (molecular weight about 12,000 daltons),[3] makes it useful in studies of cladistics.[4] Cytochrome c has been studied for the glimpse it gives into evolutionary biology.

Cytochrome c has a primary structure consisting of a chain of about 100 amino acids. Many higher-order organisms possess a chain of 104 amino acids.[5] The sequence of cytochrome c in humans is identical to that of chimpanzees (our closest relatives), but differs from that of horses.[6]

Cytochrome c has an amino acid sequence that is highly conserved in eukaryotes, varying by only a few residues. In more than thirty species tested in one study, 34 of the 104 amino acids were conserved (identical at their characteristic position).[7] For example, human cytochrome oxidase reacted with wheat cytochrome c, in vitro; which held true for all pairs of species tested.[7] In addition, the redox potential of +0.25 volts is the same in all cytochrome c molecules studied.[7]

Structure

Tunafish cytochrome c crystals (~5 mm long) grown by liquid–liquid diffusion under microgravity conditions in outer space.[8]

Cytochrome c belongs to class I of the c-type cytochrome family[9] and contains a characteristic CXXCH (cysteine-any-any-cysteine-histidine) amino acid motif that binds heme.[10] This motif is located towards the N-terminus of the peptide chain and contains a histidine as the 5th ligand of the heme iron. The 6th ligand is provided by a methionine residue found towards the C-terminus. The protein backbone is folded into five α-helices that are numbered α1-α5 from N-terminus to C-terminus. Helices α3, α4 and α5 are referred to as 50s, 60s and 70s helices, respectively, when referring to mitochondrial cytochrome c.[11]

Heme c

Structure of heme c

While most heme proteins are attached to the prosthetic group through iron ion ligation and tertiary interactions, the heme group of cytochrome c makes thioether bonds with two cysteine side chains of the protein.[12] One of the main properties of heme c, which allows cytochrome c to have variety of functions, is its ability to have different reduction potentials in nature. This property determines the kinetics and thermodynamics of an electron transfer reaction.[13]

Dipole moment

The dipole moment has an important role in orienting proteins to the proper directions and enhancing their abilities to bind to other molecules.[14][15] The dipole moment of cytochrome c results from a cluster of negatively charged amino acid side chains at the "back" of the enzyme.[15] Despite variations in the number of bound heme groups and variations in sequence, the dipole moment of vertebrate cytochromes c is remarkably conserved. For example, vertebrate cytochromes c all have a dipole moment of approximately 320 debye while cytochromes c of plants and insects have a dipole moment of approximately 340 debye.[15]

Function

Electron transport chain

Main page: Biology:Electron transport chain

Cytochrome c is an essential component of the respiratory electron transport chain in mitochondria. The heme group of cytochrome c accepts electrons from the bc1 Complex III and transports them to Complex IV, while it transfers energy in the opposite direction.

Cytochrome c can also catalyze several redox 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.

A bacterial cytochrome c functions as a nitrite reductase.[16]

Role in apoptosis

Cytochrome c was also discovered in 1996 by Xiaodong Wang to have an intermediate role 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.[17]

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.[18]

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.[19] 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.

Inhibition of apoptosis

One of the ways cell apoptosis is activated is by release of cytochrome c from the mitochondria into cytosol. A study has shown that cells are able to protect themselves from apoptosis by blocking the release of cytochrome c using Bcl-xL.[20] Another way that cells can control apoptosis is by phosphorylation of Tyr48, which would turn cytochrome c into an anti-apoptotic switch.[21]

As an antioxidative enzyme

Removal of O2− and H2O2 by cytochrome c

In addition to its well-known roles in the electron transport chain and cell apoptosis, according to a recent study cytochrome c can also act as an antioxidative enzyme in the mitochondria; it does so by removing superoxide (O2–) and hydrogen peroxide (H2O2) from mitochondria.[22] Therefore, not only is cytochrome c required in the mitochondria for cellular respiration, but it is also needed in the mitochondria to limit the production of O2– and H2O2.[22]

Extramitochondrial localisation

Cytochrome c is widely believed to be localised solely in the mitochondrial intermembrane space under normal physiological conditions.[23] The release of cytochrome c from mitochondria to the cytosol, where it activates the caspase family of proteases, is believed to be the primary trigger leading to the onset of apoptosis.[24] 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.[25][26] However, detailed immuno-electronmicroscopic 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.[27] 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 localisation of cytochrome c was shown to be specific as it was completely abolished upon adsorption of the primary antibody with purified cytochrome c.[27] Besides cytochrome c, extramitochondrial localisation has also been observed for large numbers of other proteins including those encoded by mitochondrial DNA.[28][29][30] This raises the possibility of the existence of yet-unidentified specific mechanisms for protein translocation from mitochondria to other cellular destinations.[30][31]

Applications

Superoxide detection

Peroxynitrous acid

Cytochrome c has been used to detect peroxide production in biological systems. As superoxide is produced, the number of oxidised cytochrome c3+ increases, and reduced cytochrome c2+ decreases.[32] However, superoxide is often produced with nitric oxide. In the presence of nitric oxide, the reduction of cytochrome c3+ is inhibited.[33] This leads to the oxidisation of cytochrome c2+ to cytochrome c3+ by peroxynitrous acid, an intermediate made through the reaction of nitric oxide and superoxide.[33] Presence of peroxynitrite or H2O2 and nitrogen dioxide NO2 in the mitochondria can be lethal since they nitrate tyrosine residues of cytochrome c, which leads to disruption of cytochrome c's function as an electron carrier in the electron transport chain.[34]

As an enzyme for Catalytic Activity

Cytochrome C has also been widely studied as an enzyme with peroxidase-like activity. Cytochrome C was conjugated to charged polymer to test its peroxidase-like activity.[35][36] Inspired from natural examples of enzyme encapsulation in protein-based cage structures (Example: Carboxysomes, Ferritin and Encapsulin), Cytochrome C was encapsulated in a 9 nm small self-assembling DNA binding protein from nutrient starved cells (Dps) protein cage using chimeric self-assembly approach. Authors observed unique catalytic activity behavior upon encapsulating enzyme inside a protein-cage, which was different from enzyme in solution. This was attributed to local microenvironment provided by Dps nanocage's interior cavity which is different than bulk.[37]

See also

References

  1. ↑ "Entrez Gene: cytochrome c". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54205. 
  2. ↑ "Cytochrome c release upon Fas receptor activation depends on translocation of full-length bid and the induction of the mitochondrial permeability transition". The Journal of Biological Chemistry 277 (12): 10073–82. March 2002. doi:10.1074/jbc.M111350200. PMID 11790791. 
  3. ↑ "Cytochrome c – Homo sapiens (Human)". P99999. UniProt Consortium. https://www.uniprot.org/uniprot/P99999#section_seq. "mass is 11,749 Daltons" 
  4. ↑ "Primary structure and evolution of cytochrome c". Proceedings of the National Academy of Sciences of the United States of America 50 (4): 672–9. October 1963. doi:10.1073/pnas.50.4.672. PMID 14077496. Bibcode: 1963PNAS...50..672M. 
  5. ↑ Amino acid sequences in cytochrome c proteins from different species , adapted from Strahler, Arthur; Science and Earth History, 1997. page 348.
  6. ↑ Genes, culture, and human evolution: a synthesis. Oxford: Blackwell. 2007. p. 79. ISBN 978-1-4051-5089-7. https://books.google.com/books?id=zdeWdF_NQhEC&q=chimpanzee+rhesus+cytochrome+c&pg=PA79. 
  7. ↑ 7.0 7.1 7.2 Stryer, Lubert (1975). Biochemistry (1st ed.). San Francisco: W.H. Freeman and Company. p. 362. ISBN 978-0-7167-0174-3. https://archive.org/details/biochemistry00stry_1/page/362. 
  8. ↑ "Microgravity protein crystallization". npj Microgravity 1: 15010. 2015. doi:10.1038/npjmgrav.2015.10. PMID 28725714. 
  9. ↑ "Sequence variability in bacterial cytochromes c". Biochimica et Biophysica Acta (BBA) - Bioenergetics 1058 (1): 42–7. May 1991. doi:10.1016/S0005-2728(05)80266-X. PMID 1646017. 
  10. ↑ "Cytochrome c assembly". IUBMB Life 65 (3): 209–16. March 2013. doi:10.1002/iub.1123. PMID 23341334. 
  11. ↑ "Metalloproteins Containing Cytochrome, Iron–Sulfur, or Copper Redox Centers" (in EN). Chemical Reviews 114 (8): 4366–4469. 2014-04-23. doi:10.1021/cr400479b. ISSN 0009-2665. PMID 24758379. 
  12. ↑ "Role of heme in structural organization of cytochrome c probed by semisynthesis". Biochemistry 38 (48): 15944–51. November 1999. doi:10.1021/bi9919089. PMID 10625461. 
  13. ↑ "Effect of cytochrome c on the generation and elimination of O2– and H2O2 in mitochondria". The Journal of Biological Chemistry 278 (4): 2356–60. January 2003. doi:10.1074/jbc.M209681200. PMID 12435729. 
  14. ↑ "The asymmetric distribution of charges on the surface of horse cytochrome c. Functional implications". The Journal of Biological Chemistry 257 (8): 4426–37. April 1982. doi:10.1016/S0021-9258(18)34740-9. PMID 6279635. 
  15. ↑ 15.0 15.1 15.2 "The dipole moment of cytochrome c". Molecular Biology and Evolution 8 (4): 545–58. July 1991. doi:10.1093/oxfordjournals.molbev.a040659. PMID 1656165. 
  16. ↑ Schneider, Jörg; Kroneck, Peter M.H. (2014). "The Production of Ammonia by Multiheme Cytochromes C". in Kroneck, Peter M.H.; Torres, Martha E. Sosa. The Metal-Driven Biogeochemistry of Gaseous Compounds in the Environment. Metal Ions in Life Sciences. 14. Springer. pp. 211–236. doi:10.1007/978-94-017-9269-1_9. ISBN 978-94-017-9268-4. 
  17. ↑ "Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c". Cell 86 (1): 147–57. July 1996. doi:10.1016/S0092-8674(00)80085-9. PMID 8689682. 
  18. ↑ "Cardiolipin oxidation sets cytochrome c free". Nature Chemical Biology 1 (4): 188–9. September 2005. doi:10.1038/nchembio0905-188. PMID 16408030. 
  19. ↑ "Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis". Nature Cell Biology 5 (12): 1051–61. December 2003. doi:10.1038/ncb1063. PMID 14608362. 
  20. ↑ "Role for Bcl-xL as an inhibitor of cytosolic cytochrome C accumulation in DNA damage-induced apoptosis". Proceedings of the National Academy of Sciences of the United States of America 94 (13): 6939–42. June 1997. doi:10.1073/pnas.94.13.6939. PMID 9192670. Bibcode: 1997PNAS...94.6939K. 
  21. ↑ "Tyrosine phosphorylation turns alkaline transition into a biologically relevant process and makes human cytochrome c behave as an anti-apoptotic switch". Journal of Biological Inorganic Chemistry 16 (8): 1155–68. December 2011. doi:10.1007/s00775-011-0804-9. PMID 21706253. 
  22. ↑ 22.0 22.1 "The chemistry and biochemistry of heme c: functional bases for covalent attachment". Natural Product Reports 25 (6): 1118–30. December 2008. doi:10.1039/b717196j. PMID 19030605. 
  23. ↑ "Protein import into mitochondria". Annual Review of Biochemistry 66: 863–917. 1997. doi:10.1146/annurev.biochem.66.1.863. PMID 9242927. 
  24. ↑ "The mitochondrial death/life regulator in apoptosis and necrosis". Annual Review of Physiology 60: 619–42. 1998. doi:10.1146/annurev.physiol.60.1.619. PMID 9558479. 
  25. ↑ "An aptamer-based bio-barcode assay with isothermal recombinase polymerase amplification for cytochrome-c detection and anti-cancer drug screening". Talanta 115: 159–65. October 2013. doi:10.1016/j.talanta.2013.04.051. PMID 24054573. 
  26. ↑ "A new quantitative assay for cytochrome c release in apoptotic cells". Cell Death and Differentiation 10 (7): 853–5. July 2003. doi:10.1038/sj.cdd.4401263. PMID 12815469. 
  27. ↑ 27.0 27.1 "Cytochrome-C localises in secretory granules in pancreas and anterior pituitary". Cell Biology International 25 (4): 331–8. 2001. doi:10.1006/cbir.2000.0651. PMID 11319839. 
  28. ↑ "Unusual Cellular Disposition of the Mitochondrial Molecular Chaperones Hsp60, Hsp70 and Hsp10". The Biology of Extracellular Molecular Chaperones. Novartis Foundation Symposia. 291. 2008. 59–68; discussion 69–73, 137–40. doi:10.1002/9780470754030.ch5. ISBN 978-0-470-75403-0. 
  29. ↑ "Localisation of mitochondrial DNA encoded cytochrome c oxidase subunits I and II in rat pancreatic zymogen granules and pituitary growth hormone granules". Histochemistry and Cell Biology 124 (5): 409–21. November 2005. doi:10.1007/s00418-005-0056-2. PMID 16133117. 
  30. ↑ 30.0 30.1 Mitochondrial proteins at unexpected cellular locations: export of proteins from mitochondria from an evolutionary perspective. International Review of Cytology. 194. 2000. pp. 133–96. doi:10.1016/s0074-7696(08)62396-7. ISBN 978-0-12-364598-2. 
  31. ↑ "Mitochondrial-matrix proteins at unexpected locations: are they exported?". Trends in Biochemical Sciences 24 (5): 174–7. May 1999. doi:10.1016/s0968-0004(99)01390-0. PMID 10322429. 
  32. ↑ "Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein)". The Journal of Biological Chemistry 244 (22): 6049–55. November 1969. doi:10.1016/S0021-9258(18)63504-5. PMID 5389100. 
  33. ↑ 33.0 33.1 "Kinetics of cytochrome c2+ oxidation by peroxynitrite: implications for superoxide measurements in nitric oxide-producing biological systems". Archives of Biochemistry and Biophysics 319 (2): 491–7. June 1995. doi:10.1006/abbi.1995.1321. PMID 7786032. 
  34. ↑ "The kinetics of the reaction of nitrogen dioxide with iron(II)- and iron(III) cytochrome c". Free Radical Biology & Medicine 69: 172–80. April 2014. doi:10.1016/j.freeradbiomed.2014.01.014. PMID 24447894. 
  35. ↑ Y. F. Zhang, Q. Wang and H. Hess, ACS Catal., 2017, 7, 2047–2051.
  36. ↑ K. R. Benson, J. Gorecki, A. Nikiforov, W. Tsui, R. M. Kasi and C. V. Kumar, Org. Biomol. Chem., 2019, 17, 4043–4048.
  37. ↑ "Cytochrome C with peroxidase-like activity encapsulated inside the small DPS protein nanocage". Journal of Materials Chemistry B 9 (14): 3168–3179. March 2021. doi:10.1039/d1tb00234a. PMID 33885621. 

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