Summary: Sel1 repeat
Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.
This is the Wikipedia entry entitled "Cytochrome c oxidase". More...
The Wikipedia text that you see displayed here is a download from Wikipedia. This means that the information we display is a copy of the information from the Wikipedia database. The button next to the article title ("Edit Wikipedia article") takes you to the edit page for the article directly within Wikipedia. You should be aware you are not editing our local copy of this information. Any changes that you make to the Wikipedia article will not be displayed here until we next download the article from Wikipedia. We currently download new content on a nightly basis.
Does Pfam agree with the content of the Wikipedia entry ?
Pfam has chosen to link families to Wikipedia articles. In some case we have created or edited these articles but in many other cases we have not made any direct contribution to the content of the article. The Wikipedia community does monitor edits to try to ensure that (a) the quality of article annotation increases, and (b) vandalism is very quickly dealt with. However, we would like to emphasise that Pfam does not curate the Wikipedia entries and we cannot guarantee the accuracy of the information on the Wikipedia page.
Editing Wikipedia articles
Before you edit for the first time
Wikipedia is a free, online encyclopedia. Although anyone can edit or contribute to an article, Wikipedia has some strong editing guidelines and policies, which promote the Wikipedia standard of style and etiquette. Your edits and contributions are more likely to be accepted (and remain) if they are in accordance with this policy.
You should take a few minutes to view the following pages:
How your contribution will be recorded
Anyone can edit a Wikipedia entry. You can do this either as a new user or you can register with Wikipedia and log on. When you click on the "Edit Wikipedia article" button, your browser will direct you to the edit page for this entry in Wikipedia. If you are a registered user and currently logged in, your changes will be recorded under your Wikipedia user name. However, if you are not a registered user or are not logged on, your changes will be logged under your computer's IP address. This has two main implications. Firstly, as a registered Wikipedia user your edits are more likely seen as valuable contribution (although all edits are open to community scrutiny regardless). Secondly, if you edit under an IP address you may be sharing this IP address with other users. If your IP address has previously been blocked (due to being flagged as a source of 'vandalism') your edits will also be blocked. You can find more information on this and creating a user account at Wikipedia.
If you have problems editing a particular page, contact us at firstname.lastname@example.org and we will try to help.
The community annotation is a new facility of the Pfam web site. If you have problems editing or experience problems with these pages please contact us.
Cytochrome c oxidase Edit Wikipedia article
|Cytochrome c oxidase|
The crystal structure of bovine cytochrome c oxidase in a phospholipid bilayer. The intermembrane space lies to top of the image. Adapted from (It is a homo dimer in this structure)
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
It is the last enzyme in the respiratory electron transport chain of mitochondria (or bacteria) located in the mitochondrial (or bacterial) membrane. It receives an electron from each of four cytochrome c molecules, and transfers them to one oxygen molecule, converting molecular oxygen to two molecules of water. In the process, it binds four protons from the inner aqueous phase to make water, and in addition translocates four protons across the membrane, helping to establish a transmembrane difference of proton electrochemical potential that the ATP synthase then uses to synthesize ATP.
- 1 Structure
- 2 Assembly
- 3 Table of conserved subunits of cytochrome c oxidase complex
- 4 Biochemistry
- 5 Inhibition
- 6 Subcellular Localization and Presence at Extramitochondrial Sites
- 7 Genetic defects and disorders
- 8 Histochemistry
- 9 Additional images
- 10 See also
- 11 References
- 12 External links
The complex is a large integral membrane protein composed of several metal prosthetic sites and 14  protein subunits in mammals. In mammals, eleven subunits are nuclear in origin, and three are synthesized in the mitochondria. The complex contains two hemes, a cytochrome a and cytochrome a3, and two copper centers, the CuA and CuB centers. In fact, the cytochrome a3 and CuB form a binuclear center that is the site of oxygen reduction. Cytochrome c, which is reduced by the preceding component of the respiratory chain (cytochrome bc1 complex, complex III), docks near the CuA binuclear center and passes an electron to it, being oxidized back to cytochrome c containing Fe3+. The reduced CuA binuclear center now passes an electron on to cytochrome a, which in turn passes an electron on to the cytochrome a3-CuB binuclear center. The two metal ions in this binuclear center are 4.5 Å apart and coordinate a hydroxide ion in the fully oxidized state.
Crystallographic studies of cytochrome c oxidase show an unusual post-translational modification, linking C6 of Tyr(244) and the ε-N of His(240) (bovine enzyme numbering). It plays a vital role in enabling the cytochrome a3- CuB binuclear center to accept four electrons in reducing molecular oxygen to water. The mechanism of reduction was formerly thought to involve a peroxide intermediate, which was believed to lead to superoxide production. However, the currently accepted mechanism involves a rapid four-electron reduction involving immediate oxygen-oxygen bond cleavage, avoiding any intermediate likely to form superoxide.
COX assembly in yeast is a complex process that is not entirely understood due to the rapid and irreversible aggregation of hydrophobic subunits that form the holoenzyme complex, as well as aggregation of mutant subunits with exposed hydrophobic patches. COX subunits are encoded in both the nuclear and mitochondrial genomes. The three subunits that form the COX catalytic core are encoded in the mitochondrial genome.
Hemes and cofactors are inserted into subunits I & II. Subunits I and IV initiate assembly. Different subunits may associate to form sub-complex intermediates that later bind to other subunits to form the COX complex. In post-assembly modifications, COX will form a homodimer. This is required for activity. Both dimers are connected by a cardiolipin molecule, which has been found to play a key role in stabilization of the holoenzyme complex. The dissociation of subunits VIIa and III in conjunction with the removal of cardiolipin results in total loss of enzyme activity. Subunits encoded in the nuclear genome are known to play a role in enzyme dimerization and stability. Mutations to these subunits eliminate COX function.
Assembly is known to occur in at least three distinct rate-determining steps. The products of these steps have been found, though specific subunit compositions have not been determined.
Synthesis and assembly of COX subunits I, II, and III are facilitated by translational activators, which interact with the 5’ untranslated regions of mitochondrial mRNA transcripts. Translational activators are encoded in the nucleus. They can operate through either direct or indirect interaction with other components of translation machinery, but exact molecular mechanisms are unclear due to difficulties associated with synthesizing translation machinery in-vitro. Though the interactions between subunits I, II, and III encoded within the mitochondrial genome make a lesser contribution to enzyme stability than interactions between bigenomic subunits, these subunits are more conserved, indicating potential unexplored roles for enzyme activity.
|No.||Subunit name||Human protein||Protein description from UniProt||Pfam family with Human protein|
|1||Cox1||COX1_HUMAN||Cytochrome c oxidase subunit 1||Pfam PF00115|
|2||Cox2||COX2_HUMAN||Cytochrome c oxidase subunit 2||Pfam PF02790, Pfam PF00116|
|3||Cox3||COX3_HUMAN||Cytochrome c oxidase subunit 3||Pfam PF00510|
|4||Cox4i1||COX41_HUMAN||Cytochrome c oxidase subunit 4 isoform 1, mitochondrial||Pfam PF02936|
|5||Cox4a2||COX42_HUMAN||Cytochrome c oxidase subunit 4 isoform 2, mitochondrial||Pfam PF02936|
|6||Cox5a||COX5A_HUMAN||Cytochrome c oxidase subunit 5A, mitochondrial||Pfam PF02284|
|7||Cox5b||COX5B_HUMAN||Cytochrome c oxidase subunit 5B, mitochondrial||Pfam PF01215|
|8||Cox6a1||CX6A1_HUMAN||Cytochrome c oxidase subunit 6A1, mitochondrial||Pfam PF02046|
|9||Cox6a2||CX6A2_HUMAN||Cytochrome c oxidase subunit 6A2, mitochondrial||Pfam PF02046|
|10||Cox6b1||CX6B1_HUMAN||Cytochrome c oxidase subunit 6B1||Pfam PF02297|
|11||Cox6b2||CX6B2_HUMAN||Cytochrome c oxidase subunit 6B2||Pfam PF02297|
|12||Cox6c||COX6C_HUMAN||Cytochrome c oxidase subunit 6C||Pfam PF02937|
|13||Cox7a1||CX7A1_HUMAN||Cytochrome c oxidase subunit 7A1, mitochondrial||Pfam PF02238|
|14||Cox7a2||CX7A2_HUMAN||Cytochrome c oxidase subunit 7A2, mitochondrial||Pfam PF02238|
|15||Cox7a3||COX7S_HUMAN||Putative cytochrome c oxidase subunit 7A3, mitochondrial||Pfam PF02238|
|16||Cox7b||COX7B_HUMAN||Cytochrome c oxidase subunit 7B, mitochondrial||Pfam PF05392|
|17||Cox7c||COX7C_HUMAN||Cytochrome c oxidase subunit 7C, mitochondrial||Pfam PF02935|
|18||Cox7r||COX7R_HUMAN||Cytochrome c oxidase subunit 7A-related protein, mitochondrial||Pfam PF02238|
|19||Cox8a||COX8A_HUMAN||Cytochrome c oxidase subunit 8A, mitochondrial P||Pfam PF02285|
|20||Cox8c||COX8C_HUMAN||Cytochrome c oxidase subunit 8C, mitochondrial||Pfam PF02285|
|1||Coa1||COA1_HUMAN||Cytochrome c oxidase assembly factor 1 homolog||Pfam PF08695|
|2||Coa3||COA3_HUMAN||Cytochrome c oxidase assembly factor 3 homolog, mitochondrial||Pfam PF09813|
|3||Coa4||COA4_HUMAN||Cytochrome c oxidase assembly factor 4 homolog, mitochondrial||Pfam PF06747|
|4||Coa5||COA5_HUMAN||Cytochrome c oxidase assembly factor 5||Pfam PF10203|
|5||Coa6||COA6_HUMAN||Cytochrome c oxidase assembly factor 6 homolog||Pfam PF02297|
|6||Coa7||COA7_HUMAN||Cytochrome c oxidase assembly factor 7,||Pfam PF08238|
|7||Cox11||COX11_HUMAN||Cytochrome c oxidase assembly protein COX11 mitochondrial||Pfam PF04442|
|8||Cox14||COX14_HUMAN||Cytochrome c oxidase assembly protein||Pfam PF14880|
|9||Cox15||COX15_HUMAN||Cytochrome c oxidase assembly protein COX15 homolog||Pfam PF02628|
|10||Cox16||COX16_HUMAN||Cytochrome c oxidase assembly protein COX16 homolog mitochondrial||Pfam PF14138|
|11||Cox17||COX17_HUMAN||Cytochrome c oxidase copper chaperone||Pfam PF05051|
|12||Cox18||COX18_HUMAN||Mitochondrial inner membrane protein (Cytochrome c oxidase assembly protein 18)||Pfam PF02096|
|13||Cox19||COX19_HUMAN||Cytochrome c oxidase assembly protein||Pfam PF06747|
|14||Cox20||COX20_HUMAN||Cytochrome c oxidase protein 20 homolog||Pfam PF12597|
- 4 Fe2+-cytochrome c + 8 H+in + O2 → 4 Fe3+-cytochrome c + 2 H2O + 4 H+out
Two electrons are passed from two cytochrome c's, through the CuA and cytochrome a sites to the cytochrome a3- CuB binuclear center, reducing the metals to the Fe2+ form and Cu+. The hydroxide ligand is protonated and lost as water, creating a void between the metals that is filled by O2. The oxygen is rapidly reduced, with two electrons coming from the Fe2+cytochrome a3, which is converted to the ferryl oxo form (Fe4+=O). The oxygen atom close to CuB picks up one electron from Cu+, and a second electron and a proton from the hydroxyl of Tyr(244), which becomes a tyrosyl radical: The second oxygen is converted to a hydroxide ion by picking up two electrons and a proton. A third electron arising from another cytochrome c is passed through the first two electron carriers to the cytochrome a3- CuB binuclear center, and this electron and two protons convert the tyrosyl radical back to Tyr, and the hydroxide bound to CuB2+ to a water molecule. The fourth electron from another cytochrome c flows through CuA and cytochrome a to the cytochrome a3- CuB binuclear center, reducing the Fe4+=O to Fe3+, with the oxygen atom picking up a proton simultaneously, regenerating this oxygen as a hydroxide ion coordinated in the middle of the cytochrome a3- CuB center as it was at the start of this cycle. The net process is that four reduced cytochrome c's are used, along with 4 protons, to reduce O2 to two water molecules.
COX exists in three conformational states: fully oxidized (pulsed), partially reduced, and fully reduced. Each inhibitor has a high affinity to a different state. In the pulsed state, both the heme a3 and the CuB nuclear centers are oxidized; this is the conformation of the enzyme that has the highest activity. A two-electron reduction initiates a conformational change that allows oxygen to bind at the active site to the partially-reduced enzyme. Four electrons bind to COX to fully reduce the enzyme. Its fully reduced state, which consists of a reduced Fe2+ at the cytochrome a3 heme group and a reduced CuB+ binuclear center, is considered the inactive or resting state of the enzyme.
Cyanide, azide, and carbon monoxide all bind to cytochrome c oxidase, thus competitively inhibiting the protein from functioning by preventing the binding of oxygen at the active site, which results in the chemical asphyxiation of cells. Higher concentrations of molecular oxygen are needed to compensate for increasing inhibitor concentrations, leading to an overall reduction in metabolic activity in the cell in the presence of an inhibitor. Other ligands, such as nitric oxide and hydrogen sulfide, can also inhibit COX by binding to regulatory sites on the enzyme, reducing the rate of cellular respiration.
Cyanide is a competitive inhibitor for COX, binding with high affinity to the partially-reduced state of the enzyme and hindering further reduction of the enzyme. In the pulsed state, cyanide binds slowly, but with high affinity. The ligand is posited to electrostatically stabilize both metals at once by positioning itself between them. A high nitric oxide concentration, such as one added exogenously to the enzyme, reverses cyanide inhibition of COX.
Nitric oxide can reversibly bind to either metal ion in the binuclear center to be oxidized to nitrite. NO and CN will compete with oxygen to bind at the site, reducing the rate of cellular respiration. Endogenous NO, however, which is produced at lower levels, augments CN inhibition. Higher levels of NO, which correlate with the existence of more enzyme in the reduced state, lead to a greater inhibition of cyanide. At these basal concentrations, NO inhibition of Complex IV is known to have beneficial effects, such as increasing oxygen levels in blood vessel tissues. The inability of the enzyme to reduce oxygen to water results in a buildup of oxygen, which can diffuse deeper into surrounding tissues. NO inhibition of Complex IV has a larger effect at lower oxygen concentrations, increasing its utility as a vasodilator in tissues of need.
Hydrogen sulfide will bind COX in a noncompetitive fashion at a regulatory site on the enzyme, similar to carbon monoxide. Sulfide has the highest affinity to either the pulsed or partially reduced states of the enzyme, and is capable of partially reducing the enzyme at the heme a3 center. It is unclear whether endogenous H2S levels are sufficient to inhibit the enzyme. There is no interaction between hydrogen sulfide and the fully reduced conformation of COX.
Methanol in methylated spirits is converted into formic acid, which also inhibits the same oxidase system. High levels of ATP can allosterically inhibit cytochrome c oxidase, binding from within the mitochondrial matrix.
Subcellular Localization and Presence at Extramitochondrial Sites
Cytochrome c oxidase has 3 subunits which are encoded by mitochondrial DNA. Of these 3 subunits encoded by mitochondrial DNA, two have been identified in extramitochondrial locations. In pancreatic acinar tissue, these subunits were found in zymogen granules. Additionally, in the anterior pituitary, relatively high amounts of these subunits were found in growth hormone secretory granules. The extramitochondrial function of these cytochrome c oxidase subunits has not yet been characterized. Besides cytochrome c oxidase subunits, extramitochondrial localization has also been observed for large numbers of other mitochondrial proteins., This raises the possibility about existence of yet unidentified specific mechanisms for protein translocation from mitochondria to other cellular destinations.
Genetic defects and disorders
Defects involving genetic mutations altering cytochrome c oxidase (COX) functionality or structure can result in severe, often fatal metabolic disorders. Such disorders usually manifest in early childhood and affect predominantly tissues with high energy demands (brain, heart, muscle). Among the many classified mitochondrial diseases, those involving dysfunctional COX assembly are thought to be the most severe.
The vast majority of COX disorders are linked to mutations in nuclear-encoded proteins referred to as assembly factors, or assembly proteins. These assembly factors contribute to COX structure and functionality, and are involved in several essential processes, including transcription and translation of mitochondrion-encoded subunits, processing of preproteins and membrane insertion, and cofactor biosynthesis and incorporation.
Currently, mutations have been identified in seven COX assembly factors: SURF1, SCO1, SCO2, COX10, COX15, COX20, COA5 and LRPPRC. Mutations in these proteins can result in altered functionality of sub-complex assembly, copper transport, or translational regulation. Each gene mutation is associated with the etiology of a specific disease, with some having implications in multiple disorders. Disorders involving dysfunctional COX assembly via gene mutations include Leigh syndrome, cardiomyopathy, leukodystrophy, anemia, and sensorineural deafness.
The increased reliance of neurons on oxidative phosphorylation for energy. facilitates the use of COX histochemistry in mapping regional brain metabolism in animals, since it establishes a direct and positive correlation between enzyme activity and neuronal activity. This can be seen in the correlation between COX enzyme amount and activity, which indicates the regulation of COX at the level of gene expression. COX distribution is inconsistent across different regions of the animal brain, but its pattern of its distribution is consistent across animals. This pattern has been observed in the monkey, mouse, and calf brain. One isozyme of COX has been consistently detected in histochemical analysis of the brain.
Such brain mapping has been accomplished in spontaneous mutant mice with cerebellar disease such as reeler and a transgenic model of Alzheimer's disease. This technique has also been used to map learning activity in animal brain.
- Cytochrome c oxidase subunit I
- Cytochrome c oxidase subunit II
- Cytochrome c oxidase subunit III
- Heme a
- Balsa E, Marco R, Perales-Clemente E, Szklarczyk R, Calvo E, Landázuri MO, Enríquez JA (September 2012). "NDUFA4 is a subunit of complex IV of the mammalian electron transport chain". Cell Metab. 16 (3): 378–86. doi:10.1016/j.cmet.2012.07.015. PMID 22902835.
- Tsukihara T, Aoyama H, Yamashita E, Tomizaki T, Yamaguchi H, Shinzawa-Itoh K, Nakashima R, Yaono R, Yoshikawa S (August 1995). "Structures of metal sites of oxidized bovine heart cytochrome c oxidase at 2.8 A". Science. 269 (5227): 1069–74. doi:10.1126/science.7652554. PMID 7652554.
- Voet, Donald (2010). Biochemistry. New York: J. Wiley & Sons. pp. 865–866. ISBN 0-470-57095-4.
- Fontanesi F, Soto IC, Horn D, Barrientos A (December 2006). "Assembly of mitochondrial cytochrome c-oxidase, a complicated and highly regulated cellular process". Am. J. Physiol., Cell Physiol. 291 (6): C1129–47. doi:10.1152/ajpcell.00233.2006. PMID 16760263.
- Khalimonchuk O, Rödel G (December 2005). "Biogenesis of cytochrome c oxidase". Mitochondrion. 5 (6): 363–88. doi:10.1016/j.mito.2005.08.002. PMID 16199211.
- Sedlák E, Robinson NC (September 15, 2015). "Destabilization of the Quaternary structure of Bovine Heart Cytochrome c Oxidase upon Removal of Tightly Bound Cardiolipin". Biochemistry. 54 (36): 5569–77. doi:10.1021/acs.biochem.5b00540. PMID 26284624.
- Herrmann JM, Woellhaf MW, Bonnefoy N (February 2013). "Control of protein synthesis in yeast mitochondria: the concept of translational activators". Biochimica et Biophysica Acta. 1833 (2): 286–294. doi:10.1016/j.bbamcr.2012.03.007. PMID 22450032.
- Soto IC, Fontanesi F, Liu J, Barrientos A (June 2012). "Biogenesis and assembly of eukaryotic cytochrome c oxidase catalytic core". Biochimica et Biophysica Acta. 1817 (6): 883–97. doi:10.1016/j.bbabio.2011.09.005. PMC . PMID 21958598.
- Aledo JC, Valverde H, Ruiz-Camacho M, Morilla L, López FD (2014). "Protein-Protein Interfaces from Cytochrome c Oxidase I Evolve Faster than Nonbonding Surfaces, yet Negative Selection Is the Driving Force". Genome Biology and Evolution. 6 (11): 3064–76. doi:10.1093/gbe/evu240. PMC . PMID 25359921.
- Zhang Z; Huang L; Shulmeister VM; Chi YI; Kim KK; Hung LW; et al. (1998). "Electron transfer by domain movement in cytochrome bc1.". Nature. 392 (6677): 677–84. doi:10.1038/33612. PMID 9565029.
- Kaila VR; Oksanen E; Goldman A; Bloch DA; Verkhovsky MI; Sundholm D; et al. (2011). "A combined quantum chemical and crystallographic study on the oxidized binuclear center of cytochrome c oxidase.". Biochim Biophys Acta. 1807 (7): 769–78. doi:10.1016/j.bbabio.2010.12.016. PMID 21211513.
- Szklarczyk R, Wanschers BF, Cuypers TD, Esseling JJ, Riemersma M, van den Brand MA, et al. (2012). "Iterative orthology prediction uncovers new mitochondrial proteins and identifies C12orf62 as the human ortholog of COX14, a protein involved in the assembly of cytochrome c oxidase.". Genome Biol. 13 (2): R12. doi:10.1186/gb-2012-13-2-r12. PMC . PMID 22356826.
- Mick DU; Dennerlein S; Wiese H; Reinhold R; Pacheu-Grau D; Lorenzi I; et al. (2012). "MITRAC links mitochondrial protein translocation to respiratory-chain assembly and translational regulation.". Cell. 151 (7): 1528–41. doi:10.1016/j.cell.2012.11.053. PMID 23260140.
- Kozjak-Pavlovic V; Prell F; Thiede B; Götz M; Wosiek D; Ott C; et al. (2014). "C1orf163/RESA1 is a novel mitochondrial intermembrane space protein connected to respiratory chain assembly.". J Mol Biol. 426 (4): 908–20. doi:10.1016/j.jmb.2013.12.001. PMID 24333015.
- Gaisne M, Bonnefoy N (2006). "The COX18 gene, involved in mitochondrial biogenesis, is functionally conserved and tightly regulated in humans and fission yeast.". FEMS Yeast Res. 6 (6): 869–82. doi:10.1111/j.1567-1364.2006.00083.x. PMID 16911509.
- Voet and Voet, Biochemistry (2011) pp.841–45
- Leavesley H, Li L, Prabhakaran K, Malmström BG (January 2008). "Interaction of cyanide and nitric oxide with cytochrome c oxidase: Implications for acute cyanide toxicity". Toxicological Sciences. 101 (1): 101–11. doi:10.1093/toxsci/kfm254. PMID 17906319.
- Alonso JR, Cardellach F, López S, Casademont J, Miró O (September 2003). "Carbon monoxide specifically inhibits cytochrome c oxidase of human mitochondrial respiratory chain". Pharmacol. Toxicol. 93 (3): 142–6. doi:10.1034/j.1600-0773.2003.930306.x. PMID 12969439.
- Nicholls P, Marshall D, Cooper C, Wilson M (October 2013). "Sulfide inhibition of and metabolism by cytochrome c oxidase". Biochm. Soc. Trans. 41 (5): 1312–16. doi:10.1042/BST20130070. PMID 24059525.
- Jensen P, Wilson MT, Aasa R, Malmström BG (December 1984). "Cyanide inhibition of cytochrome c oxidase. A rapid-freeze e.p.r. investigation". Biochem J. 224 (3): 829–837. doi:10.1042/bj2240829. PMC . PMID 6098268.
- Gladwin MT, Shiva S (May 22, 2009). "The ligand binding battle at cytochrome c oxidase: how NO regulates oxygen gradients in tissue". Circ Res. 104 (10): 1136–8. doi:10.1161/CIRCRESAHA.109.198911. PMID 19461104.
- Arnold S, Kadenbach B (October 1997). "Cell respiration s controlled by ATP, an allosteric inhibitor of cytochrome-c oxidase.". Eur J Biochem: 350–254.
- Sadacharan, S. K., Singh, B., Bowes, T. and Gupta, R. S. (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. 124:409-421.
- Gupta, R. S., Ramachandra, N. B., Bowes, T. and Singh, B. (2008) Unusual cellular disposition of the mitochondrial molecular chaperones Hsp60, Hsp70 and Hsp10. Novartis Found Symp. 291: 59-68.
- Soltys BJ, Gupta RS (1999). "Mitochondrial proteins at unexpected cellular locations: export of proteins from mitochondria from an evolutionary perspective". International Review of Cytology. 94: 133–196.
- Soltys BJ, Gupta RS (1999). "Mitochondrial proteins at unexpected locations: Are they exported?". Trends Biochem. Sci. 24: 174–177. doi:10.1016/s0968-0004(99)01390-0. PMID 10322429.
- Pecina P, Houstková H, Hansíková H, Zeman J, Houstek J (2004). "Genetic defects of cytochrome c oxidase assembly" (PDF). Physiol Res. 53 Suppl 1: S213–23. PMID 15119951.
- Zee JM, Glerum DM (December 2006). "Defects in cytochrome oxidase assembly in humans: lessons from yeast". Biochem. Cell Biol. 84 (6): 859–69. doi:10.1139/o06-201. PMID 17215873.
- Johar K, Priya A, Dhar S, Liu Q, Wong-Riley MT (November 2013). "Neuron-specific specificity protein 4 bigenomically regulates the transcription of all mitochondria and nucleus-encoded cytochrome c oxidase subunit genes in neurons". J Neurochem. 127 (4): 496–508. doi:10.1111/jnc.12433. PMC . PMID 24032355.
- Wong-Riley MT. (1989). "Cytochrome oxidase: an endogenous metabolic marker for neuronal activity.". Trends Neurosci. 12 (3): 94–111. doi:10.1016/0166-2236(89)90165-3. PMID 2469224.
- Hevner RF, Wong-Riley MT (November 1989). "Brain cytochrome c oxidase: purification, antibody production, and immunohistochemical/histochemical correlations in the CNS". J Neurosci. 9 (11): 3884–98. PMID 2555458.
- Strazielle C, Hayzoun K, Derer M, Mariani J, Lalonde R (April 2006). "Regional brain variations of cytochrome oxidase activity in Relnrl-orl mutant mice.". J. Neurosci. Res. 83 (5): 821–31. doi:10.1002/jnr.20772. PMID 16511878.
- Strazielle C, Sturchler-Pierrat C, Staufenbiel M, Lalonde R (2003). "Regional brain cytochrome oxidase activity in beta-amyloid precursor protein transgenic mice with the Swedish mutation.". Neuroscience. 118 (4): 1151–63. doi:10.1016/S0306-4522(03)00037-X. PMID 12732258.
- Conejo NM, González-Pardo H, Gonzalez-Lima F, Arias JL (2010). "Spatial learning of the water maze: progression of brain circuits mapped with cytochrome oxidase histochemistry.". Neurobiol. Learn. Mem. 93 (3): 362–71. doi:10.1016/j.nlm.2009.12.002. PMID 19969098.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Sel1 repeat Provide feedback
This short repeat is found in the Sel1 protein . It is related to TPR repeats.
Grant B, Greenwald I; , Genetics 1996;143:237-247.: The Caenorhabditis elegans sel-1 gene, a negative regulator of lin-12 and glp-1, encodes a predicted extracellular protein. PUBMED:8722778 EPMC:8722778
This tab holds annotation information from the InterPro database.
InterPro entry IPR006597
Sel1-like repeats are tetratricopeptide repeat sequences originally identified in a Caenorhabditis elegans receptor molecule which is a key negative regulator of the Notch pathway [PUBMED:8722778]. Mammalian homologues have since been identified although these mainly pancreatic proteins have yet to have a function assigned.
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
Tetratricopeptide-like repeats are found in a numerous and diverse proteins involved in such functions as cell cycle regulation, transcriptional control, mitochondrial and peroxisomal protein transport, neurogenesis and protein folding.
The clan contains the following 132 members:Adaptin_N Alkyl_sulf_dimr ANAPC3 ANAPC5 API5 Arm Arm_2 Arm_3 B56 BTAD CAS_CSE1 ChAPs CLASP_N Clathrin Clathrin-link Clathrin_H_link Clathrin_propel Cnd1 Cnd3 Coatomer_E Cohesin_HEAT Cohesin_load COPI_C CRM1_C Cse1 DNA_alkylation Drf_FH3 Drf_GBD DUF1822 DUF2019 DUF2225 DUF3385 DUF3458 DUF3808 DUF3856 DUF4042 DUF924 EST1 EST1_DNA_bind FAT Fis1_TPR_C Fis1_TPR_N Foie-gras_1 GUN4_N HAT HEAT HEAT_2 HEAT_EZ HEAT_PBS HemY_N IBB IBN_N IFRD KAP Leuk-A4-hydro_C LRV LRV_FeS MA3 MIF4G MIF4G_like MIF4G_like_2 Mo25 MRP-S27 NARP1 Neurochondrin Nipped-B_C Nro1 NSF Paf67 ParcG PC_rep PHAT PI3Ka PknG_TPR PPP5 PPR PPR_1 PPR_2 PPR_3 PPR_long PPTA Proteasom_PSMB PUF Rab5-bind Rapsyn_N RPN7 Sel1 SHNi-TPR SNAP SPO22 SRP_TPR_like ST7 Suf SusD SusD-like SusD-like_2 SusD-like_3 TAF6_C TAL_effector TAtT Tcf25 TIP120 TOM20_plant TPR_1 TPR_10 TPR_11 TPR_12 TPR_14 TPR_15 TPR_16 TPR_17 TPR_18 TPR_19 TPR_2 TPR_20 TPR_21 TPR_3 TPR_4 TPR_5 TPR_6 TPR_7 TPR_8 TPR_9 Upf2 V-ATPase_H_C V-ATPase_H_N Vac14_Fab1_bd Vitellogenin_N Vps39_1 W2 Xpo1 YfiO
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:||Pfam-B_49 (Release 17.0)|
|Number in seed:||170|
|Number in full:||46004|
|Average length of the domain:||35.20 aa|
|Average identity of full alignment:||27 %|
|Average coverage of the sequence by the domain:||35.93 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 17690987 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||10|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 2 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Sel1 domain has been found. There are 26 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
Loading structure mapping...