Cytochrome c

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Cytochrome c, somatic
Cytochrome C.png
Three-dimensional structure of cytochrome c (green) with a heme molecule coordinating a central Iron atom (orange).
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CYCS ; CYC; HCS; THC4
External IDs OMIM123970 MGI88578 HomoloGene133055 GeneCards: CYCS Gene
RNA expression pattern
PBB GE CYCS 208905 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 54205 13063
Ensembl ENSG00000172115 ENSMUSG00000058927
UniProt P99999 P62897
RefSeq (mRNA) NM_018947 NM_007808
RefSeq (protein) NP_061820 NP_031834
Location (UCSC) Chr 7:
25.16 – 25.16 Mb
Chr 19:
24.88 – 24.88 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.[1][2]

Function[edit]

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).[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.

Species distribution[edit]

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),[3] makes it useful in studies of cladistics.[4] Its primary structure consists of a chain of about 100 amino acids. Many higher order organisms possess a chain of 104 amino acids.[5] The cytochrome c molecule has been studied for the glimpse it gives into evolutionary biology. Its amino acid sequence is highly conserved in mammals differing by only a few residues. For example, the sequences of cytochrome c in humans is identical to that of a chimpanzees (our closest relatives), but differs more from that of horses. [6]

Classes[edit]

In 1991 R. P. Ambler recognized four classes of cytochrome c:[7]

  • 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[edit]

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.[8]

Role in apoptosis[edit]

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.[9]

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. [10]

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.[11] 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[edit]

Cytochrome c is widely believed to be localized solely in the mitochondrial intermembrane space under normal physiological conditions.[12] 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.[13] 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.[14] 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 completed abolished upon adsorption of the primary antibody with the purified cytochrome c.[14] 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.[14] Besides cytochrome c, extramitochondrial localization has also been observed for large numbers of other proteins including those encoded by mitochondrial DNA.[15][16][17] This raises the possibility about existence of yet unidentified specific mechanisms for protein translocation from mitochondria to other cellular destinations.[17][18]

See also[edit]

References[edit]

  1. ^ a b "Entrez Gene: cytochrome c". 
  2. ^ Tafani M, Karpinich NO, Hurster KA, Pastorino JG, Schneider T, Russo MA, Farber JL (March 2002). "Cytochrome c release upon Fas receptor activation depends on translocation of full-length bid and the induction of the mitochondrial permeability transition". J. Biol. Chem. 277 (12): 10073–82. doi:10.1074/jbc.M111350200. PMID 11790791. 
  3. ^ "Cytochrome c - Homo sapiens (Human)". P99999. UniProt Consortium. "mass is 11,749 Daltons" 
  4. ^ Margoliash E (October 1963). "Primary structure and evolution of cytochrome c". Proc. Natl. Acad. Sci. U.S.A. 50: 672–9. doi:10.1073/pnas.50.4.672. PMC 221244. PMID 14077496. 
  5. ^ Amino acid sequences in cytochrome c proteins from different species, adapted from Strahler, Arthur; Science and Earth History, 1997. page 348.
  6. ^ Lurquin PF, Stone L, Cavalli-Sforza LL (2007). Genes, culture, and human evolution: a synthesis. Oxford: Blackwell. p. 79. ISBN 1-4051-5089-0. 
  7. ^ Ambler RP (May 1991). "Sequence variability in bacterial cytochromes c". Biochim. Biophys. Acta 1058 (1): 42–7. doi:10.1016/S0005-2728(05)80266-X. PMID 1646017. 
  8. ^ Silveira PC, Streck EL, Pinho RA. (2005). "Cellular effects of low power laser therapy can be mediated by nitric oxide.". Lasers Surg Med. 36 (4): 307–14. doi:10.1002/lsm.20148. PMID 15739174. 
  9. ^ Liu X, Kim CN, Yang J, Jemmerson R, Wang X (July 1996). "Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c". Cell 86 (1): 147–57. doi:10.1016/S0092-8674(00)80085-9. PMID 8689682. 
  10. ^ Orrenius S, Zhivotovsky B (September 2005). "Cardiolipin oxidation sets cytochrome c free". Nat. Chem. Biol. 1 (4): 188–9. doi:10.1038/nchembio0905-188. PMID 16408030. 
  11. ^ Boehning D, Patterson RL, Sedaghat L, Glebova NO, Kurosaki T, Snyder SH (December 2003). "Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis". Nat. Cell Biol. 5 (12): 1051–61. doi:10.1038/ncb1063. PMID 14608362. 
  12. ^ Neupert W (1997). "Protein import into mitochondria". Annu. Rev. Biochem. 66: 863–917. doi:10.1146/annurev.biochem.66.1.863. PMID 9242927. 
  13. ^ Kroemer G, Dallaporta B, Resche-Rigon M (1998). "The mitochondrial death/life regulator in apoptosis and necrosis". Annu. Rev. Physiol. 60: 619–42. doi:10.1146/annurev.physiol.60.1.619. PMID 9558479. 
  14. ^ a b c Soltys BJ, Andrews DW, Jemmerson R, Gupta RS (2001). "Cytochrome-C localizes in secretory granules in pancreas and anterior pituitary". Cell Biol. Int. 25 (4): 331–8. doi:10.1006/cbir.2000.0651. PMID 11319839. 
  15. ^ Gupta RS, Ramachandra NB, Bowes T, Singh B (2008). "Unusual cellular disposition of the mitochondrial molecular chaperones Hsp60, Hsp70 and Hsp10". Novartis Found. Symp. 291: 59–68; discussion 69–73, 137–40. doi:10.1002/9780470754030.ch5. PMID 18575266. 
  16. ^ Sadacharan SK, Singh B, Bowes T, Gupta RS (November 2005). "Localization of mitochondrial DNA encoded cytochrome c oxidase subunits I and II in rat pancreatic zymogen granules and pituitary growth hormone granules". Histochem. Cell Biol. 124 (5): 409–21. doi:10.1007/s00418-005-0056-2. PMID 16133117. 
  17. ^ a b Soltys BJ, Gupta RS (2000). "Mitochondrial proteins at unexpected cellular locations: export of proteins from mitochondria from an evolutionary perspective". Int. Rev. Cytol. 194: 133–96. doi:10.1016/s0074-7696(08)62396-7. PMID 10494626. 
  18. ^ Soltys BJ, Gupta RS (May 1999). "Mitochondrial-matrix proteins at unexpected locations: are they exported?". Trends Biochem. Sci. 24 (5): 174–7. doi:10.1016/s0968-0004(99)01390-0. PMID 10322429. 

Further reading[edit]

  • Kumarswamy R and Chandna S (2009). "Putative partners in Bax mediated cytochrome-c release: ANT, CypD, VDAC or none of them?". Mitochondrion. 9 (1): 1–8. doi:10.1016/j.mito.2008.10.003. PMID 18992370. 
  • Skulachev VP (1998). "Cytochrome c in the apoptotic and antioxidant cascades.". FEBS Lett. 423 (3): 275–80. doi:10.1016/S0014-5793(98)00061-1. PMID 9515723. 
  • Mannella CA (1998). "Conformational changes in the mitochondrial channel protein, VDAC, and their functional implications.". J. Struct. Biol. 121 (2): 207–18. doi:10.1006/jsbi.1997.3954. PMID 9615439. 
  • Ferri KF, Jacotot E, Blanco J, Esté JA, Kroemer G (2000). "Mitochondrial control of cell death induced by HIV-1-encoded proteins". Ann. N. Y. Acad. Sci. 926: 149–64. doi:10.1111/j.1749-6632.2000.tb05609.x. PMID 11193032. 
  • Britton RS, Leicester KL, Bacon BR (2002). "Iron toxicity and chelation therapy". Int. J. Hematol. 76 (3): 219–28. doi:10.1007/BF02982791. PMID 12416732. 
  • Haider N, Narula N, Narula J (2003). "Apoptosis in heart failure represents programmed cell survival, not death, of cardiomyocytes and likelihood of reverse remodeling". J. Card. Fail. 8 (6 Suppl): S512–7. doi:10.1054/jcaf.2002.130034. PMID 12555167. 
  • Castedo M, Perfettini JL, Andreau K, Roumier T, Piacentini M, Kroemer G (December 2003). "Mitochondrial apoptosis induced by the HIV-1 envelope". Ann. N. Y. Acad. Sci. 1010: 19–28. doi:10.1196/annals.1299.004. PMID 15033690. 
  • Ng S, Smith MB, Smith HT, Millett F (1977). "Effect of modification of individual cytochrome c lysines on the reaction with cytochrome b5". Biochemistry 16 (23): 4975–8. doi:10.1021/bi00642a006. PMID 199233. 
  • Lynch SR, Sherman D, Copeland RA (1992). "Cytochrome c binding affects the conformation of cytochrome a in cytochrome c oxidase". J. Biol. Chem. 267 (1): 298–302. PMID 1309738. 
  • Garber EA, Margoliash E (1990). "Interaction of cytochrome c with cytochrome c oxidase: an understanding of the high- to low-affinity transition". Biochim. Biophys. Acta 1015 (2): 279–87. doi:10.1016/0005-2728(90)90032-Y. PMID 2153405. 
  • Bedetti CD (1985). "Immunocytochemical demonstration of cytochrome c oxidase with an immunoperoxidase method: a specific stain for mitochondria in formalin-fixed and paraffin-embedded human tissues". J. Histochem. Cytochem. 33 (5): 446–52. doi:10.1177/33.5.2580882. PMID 2580882. 
  • Tanaka Y, Ashikari T, Shibano Y, Amachi T, Yoshizumi H, Matsubara H (June 1988). "Construction of a human cytochrome c gene and its functional expression in Saccharomyces cerevisiae". J. Biochem. 103 (6): 954–61. PMID 2844747. 
  • Evans MJ, Scarpulla RC (1989). "The human somatic cytochrome c gene: two classes of processed pseudogenes demarcate a period of rapid molecular evolution". Proc. Natl. Acad. Sci. U.S.A. 85 (24): 9625–9. doi:10.1073/pnas.85.24.9625. PMC 282819. PMID 2849112. 
  • Passon PG, Hultquist DE (1972). "Soluble cytochrome b 5 reductase from human erythrocytes". Biochim. Biophys. Acta 275 (1): 62–73. doi:10.1016/0005-2728(72)90024-2. PMID 4403130. 
  • Dowe RJ, Vitello LB, Erman JE (1984). "Sedimentation equilibrium studies on the interaction between cytochrome c and cytochrome c peroxidase". Arch. Biochem. Biophys. 232 (2): 566–73. doi:10.1016/0003-9861(84)90574-5. PMID 6087732. 
  • Michel B, Bosshard HR (1984). "Spectroscopic analysis of the interaction between cytochrome c and cytochrome c oxidase". J. Biol. Chem. 259 (16): 10085–91. PMID 6088481. 
  • Broger C, Nałecz MJ, Azzi A (1980). "Interaction of cytochrome c with cytochrome bc1 complex of the mitochondrial respiratory chain". Biochim. Biophys. Acta 592 (3): 519–27. doi:10.1016/0005-2728(80)90096-1. PMID 6251869. 
  • Smith HT, Ahmed AJ, Millett F (1981). "Electrostatic interaction of cytochrome c with cytochrome c1 and cytochrome oxidase". J. Biol. Chem. 256 (10): 4984–90. PMID 6262312. 
  • Geren LM, Millett F (1981). "Fluorescence energy transfer studies of the interaction between adrenodoxin and cytochrome c". J. Biol. Chem. 256 (20): 10485–9. PMID 6270113. 
  • Favre B, Zolnierowicz S, Turowski P, Hemmings BA (1994). "The catalytic subunit of protein phosphatase 2A is carboxyl-methylated in vivo". J. Biol. Chem. 269 (23): 16311–7. PMID 8206937. 
  • Gao B, Eisenberg E, Greene L (1996). "Effect of constitutive 70-kDa heat shock protein polymerization on its interaction with protein substrate". J. Biol. Chem. 271 (28): 16792–7. doi:10.1074/jbc.271.28.16792. PMID 8663341. 

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External links[edit]