Cytochrome c oxidase subunit III

Last updated
COX3
Identifiers
Aliases COX3 , COIII, MTCO3, Cytochrome c oxidase subunit III, cytochrome c oxidase III
External IDs OMIM: 516050 MGI: 102502 HomoloGene: 5014 GeneCards: COX3
Orthologs
SpeciesHumanMouse
Entrez

4514

17710

Ensembl

ENSG00000198938

ENSMUSG00000064358

UniProt

P00414

P00416

RefSeq (mRNA)

n/a

n/a

RefSeq (protein)

n/a

NP_904334

Location (UCSC)n/a Chr M: 0.01 – 0.01 Mb
PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse
Location of the MT-CO3 gene in the human mitochondrial genome. MT-CO3 is one of the three cytochrome c oxidase subunit mitochondrial genes (orange boxes). Map of the human mitochondrial genome.svg
Location of the MT-CO3 gene in the human mitochondrial genome. MT-CO3 is one of the three cytochrome c oxidase subunit mitochondrial genes (orange boxes).
Cytochrome c oxidase subunit III
PDB 1occ EBI.jpg
Structure of the 13-subunit oxidized cytochrome c oxidase. [4]
Identifiers
SymbolCOX3
Pfam PF00510
InterPro IPR000298
PROSITE PDOC50253
SCOP2 1occ / SCOPe / SUPFAM
TCDB 3.D.4
OPM superfamily 4
OPM protein 1v55
CDD cd01665

Cytochrome c oxidase subunit III (COX3) is an enzyme that in humans is encoded by the MT-CO3 gene. [5] It is one of main transmembrane subunits of cytochrome c oxidase. Cytochrome c oxidase subunit III is also one of the three mitochondrial DNA (mtDNA) encoded subunits (MT-CO1, MT-CO2, MT-CO3) of respiratory complex IV. Variants of MT-CO3 have been associated with isolated myopathy, severe encephalomyopathy, Leber hereditary optic neuropathy, mitochondrial complex IV deficiency, and recurrent myoglobinuria . [6] [7] [8]

Contents

Structure

The MT-CO3 gene produces a 30 kDa protein composed of 261 amino acids. [9] [10] COX3, the protein encoded by this gene, is a member of the cytochrome c oxidase subunit 3 family. This protein is located on the inner mitochondrial membrane. COX3 is a multi-pass transmembrane protein: in human, it contains 7 transmembrane domains at positions 15-35, 42-59, 81-101, 127-147, 159-179, 197-217, and 239-259. [7] [8]

Function

Cytochrome c oxidase (EC 1.9.3.1) is the terminal enzyme of the respiratory chain of mitochondria and many aerobic bacteria. It catalyzes the transfer of electrons from reduced cytochrome c to molecular oxygen:

4 cytochrome c+2 + 4 H+ + O2 4 cytochrome c+3 + 2 H2O

This reaction is coupled to the pumping of four additional protons across the mitochondrial or bacterial membrane. [11] [12]

Cytochrome c oxidase is an oligomeric enzymatic complex that is located in the mitochondrial inner membrane of eukaryotes and in the plasma membrane of aerobic prokaryotes. The core structure of prokaryotic and eukaryotic cytochrome c oxidase contains three common subunits, I, II and III. In prokaryotes, subunits I and III can be fused and a fourth subunit is sometimes found, whereas in eukaryotes there are a variable number of additional small subunits. [13]

As the bacterial respiratory systems are branched, they have a number of distinct terminal oxidases, rather than the single cytochrome c oxidase present in the eukaryotic mitochondrial systems. Although the cytochrome o oxidases do not catalyze the cytochrome c but the quinol (ubiquinol) oxidation they belong to the same haem-copper oxidase superfamily as cytochrome c oxidases. Members of this family share sequence similarities in all three core subunits: subunit I is the most conserved subunit, whereas subunit II is the least conserved. [14] [15] [16]

Clinical significance

Mutations in mtDNA-encoded cytochrome c oxidase subunit genes have been observed to be associated with isolated myopathy, severe encephalomyopathy, Leber hereditary optic neuropathy, mitochondrial complex IV deficiency, and recurrent myoglobinuria . [6] [7] [8]

Leber hereditary optic neuropathy (LHON)

LHON is a maternally inherited disease resulting in acute or subacute loss of central vision, due to optic nerve dysfunction. Cardiac conduction defects and neurological defects have also been described in some patients. LHON results from primary mitochondrial DNA mutations affecting the respiratory chain complexes. Mutations at positions 9438 and 9804, which result in glycine-78 to serine and alanine-200 to threonine amino acid changes, have been associated with this disease. [17] [7] [8]

Mitochondrial complex IV deficiency (MT-C4D)

Complex IV deficiency (COX deficiency) is a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Features include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development, mental retardation, lactic acidemia, encephalopathy, ataxia, and cardiac arrhythmia. Some affected individuals manifest a fatal hypertrophic cardiomyopathy resulting in neonatal death and a subset of patients manifest Leigh syndrome. The mutations G7970T and G9952A have been associated with this disease. [6] [18] [7] [8]

Recurrent myoglobinuria mitochondrial (RM-MT)

Recurrent myoglobinuria is characterized by recurrent attacks of rhabdomyolysis (necrosis or disintegration of skeletal muscle) associated with muscle pain and weakness, and followed by excretion of myoglobin in the urine. It has been associated with mitochondrial complex IV deficiency. [19] [7] [8]

Subfamilies

Interactions

COX3 has been shown to have 15 binary protein-protein interactions including 8 co-complex interactions. COX3 appears to interact with SNCA, KRAS, RAC1, and HSPB2. [20]

Related Research Articles

MT-RNR1

Mitochondrially encoded 12S ribosomal RNA, also known as Mitochondrial-derived peptide MOTS-c or Mitochondrial open reading frame of the 12S rRNA-c is the SSU rRNA of the mitochondrial ribosome. In humans, 12S is encoded by the MT-RNR1 gene and is 959 nucleotides long. MT-RNR1 is one of the 37 genes contained in animal mitochondria genomes. Their 2 rRNA, 22 tRNA and 13 mRNA genes are very useful in phylogenetic studies, in particular the 12S and 16S rRNAs. The 12S rRNA is the mitochondrial homologue of the prokaryotic 16S and eukaryotic nuclear 18S ribosomal RNAs. Mutations in the MT-RNR1 gene may be associated with hearing loss.

Cytochrome c oxidase subunit I Enzyme of the respiratory chain encoded by the mitochondrial genome

Cytochrome c oxidase I (COX1) also known as mitochondrially encoded cytochrome c oxidase I (MT-CO1) is a protein that in humans is encoded by the MT-CO1 gene. In other eukaryotes, the gene is called COX1, CO1, or COI. Cytochrome c oxidase I is the main subunit of the cytochrome c oxidase complex. Mutations in MT-CO1 have been associated with Leber's hereditary optic neuropathy (LHON), acquired idiopathic sideroblastic anemia, Complex IV deficiency, colorectal cancer, sensorineural deafness, and recurrent myoglobinuria.

Cytochrome c oxidase subunit II Enzyme of the respiratory chain encoded by the mitochondrial genome

Cytochrome c oxidase subunit 2, also known as cytochrome c oxidase polypeptide II, is a protein that in humans is encoded by the MT-CO2 gene. Cytochrome c oxidase subunit II, abbreviated COXII, COX2, COII, or MT-CO2, is the second subunit of cytochrome c oxidase. It is also one of the three mitochondrial DNA (mtDNA) encoded subunits of respiratory complex IV.

MT-CYB A mitochondrial protein-coding gene whose product is involved in the respiratory chain

Cytochrome b is a protein that in humans is encoded by the MT-CYB gene. Its gene product is a subunit of the respiratory chain protein ubiquinol–cytochrome c reductase, which consists of the products of one mitochondrially encoded gene, MT-CYB, and ten nuclear genes—UQCRC1, UQCRC2, CYC1, UQCRFS1, UQCRB, "11kDa protein", UQCRH, Rieske protein presequence, "cyt c1 associated protein", and Rieske-associated protein.

SCO1

Protein SCO1 homolog, mitochondrial, also known as SCO1, cytochrome c oxidase assembly protein, is a protein that in humans is encoded by the SCO1 gene. SCO1 localizes predominantly to blood vessels, whereas SCO2 is barely detectable, as well as to tissues with high levels of oxidative phosphorylation. The expression of SCO2 is also much higher than that of SCO1 in muscle tissue, while SCO1 is expressed at higher levels in liver tissue than SCO2. Mutations in both SCO1 and SCO2 are associated with distinct clinical phenotypes as well as tissue-specific cytochrome c oxidase deficiency.

COX17

Cytochrome c oxidase copper chaperone is a protein that in humans is encoded by the COX17 gene.

COX4I1

Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1) is an enzyme that in humans is encoded by the COX4I1 gene. COX4I1 is a nuclear-encoded isoform of cytochrome c oxidase (COX) subunit 4. Cytochrome c oxidase is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane, acting as the terminal enzyme of the mitochondrial respiratory chain. Antibodies against COX4 can be used to identify the inner membrane of mitochondria in immunfluorescence studies. Mutations in COX4I1 have been associated with COX deficiency and Fanconi anemia.

COX6B1

Cytochrome c oxidase subunit 6B1 is an enzyme that in humans is encoded by the COX6B1 gene. Cytochrome c oxidase 6B1 is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain. Mutations of the COX6B1 gene are associated with severe infantile encephalomyopathy and mitochondrial complex IV deficiency (MT-C4D).

COX10

Protoheme IX farnesyltransferase, mitochondrial is an enzyme that in humans is encoded by the COX10 gene. Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene, COX10, encodes heme A: farnesyltransferase, which is not a structural subunit but required for the expression of functional COX and functions in the maturation of the heme A prosthetic group of COX. A gene mutation, which results in the substitution of a lysine for an asparagine (N204K), is identified to be responsible for cytochrome c oxidase deficiency. In addition, this gene is disrupted in patients with CMT1A duplication and with HNPP deletion.

COX6A1

Cytochrome c oxidase subunit 6A1, mitochondrial is a protein that in humans is encoded by the COX6A1 gene. Cytochrome c oxidase 6A1 is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain. A mutation of the COX6A1 gene is associated with a recessive axonal or mixed form of Charcot-Marie-Tooth disease.

UQCRB

Ubiquinol-cytochrome c reductase binding protein, also known as UQCRB, Complex III subunit 7, QP-C, or Ubiquinol-cytochrome c reductase complex 14 kDa protein is a protein which in humans is encoded by the UQCRB gene. This gene encodes a subunit of the ubiquinol-cytochrome c oxidoreductase complex, which consists of one mitochondrial-encoded and 10 nuclear-encoded subunits. Mutations in this gene are associated with mitochondrial complex III deficiency. Alternatively spliced transcript variants have been found for this gene. Related pseudogenes have been identified on chromosomes 1, 5 and X.

COX7B

Cytochrome c oxidase subunit 7B, mitochondrial (COX7B) is an enzyme that in humans is encoded by the COX7B gene. COX7B is a nuclear-encoded subunit of cytochrome c oxidase (COX). Cytochrome c oxidase is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane, acting as the terminal enzyme of the mitochondrial respiratory chain. Work with Oryzias latices has linked disruptions in COX7B with microphthalmia with linear skin lesions (MLS), microcephaly, and mitochondrial disease. Clinically, mutations in COX7B have been associated with linear skin defects with multiple congenital anomalies.

COX7A2L

Cytochrome c oxidase subunit 7A-related protein, mitochondrial is an enzyme that in humans is encoded by the COX7A2L gene.

COX15

Cytochrome c oxidase assembly protein COX15 homolog (COX15), also known as heme A synthase, is a protein that in humans is encoded by the COX15 gene. This protein localizes to the inner mitochondrial membrane and involved in heme A biosynthesis. COX15 is also part of a three-component mono-oxygenase that catalyses the hydroxylation of the methyl group at position eight of the protoheme molecule. Mutations in this gene has been reported in patients with hypertrophic cardiomyopathy as well as Leigh syndrome, and characterized by delayed onset of symptoms, hypotonia, feeding difficulties, failure to thrive, motor regression, and brain stem signs.

Mitochondrially encoded tRNA glutamic acid also known as MT-TE is a transfer RNA which in humans is encoded by the mitochondrial MT-TE gene. MT-TE is a small 69 nucleotide RNA that transfers the amino acid glutamic acid to a growing polypeptide chain at the ribosome site of protein synthesis during translation.

Mitochondrially encoded tRNA leucine 2 (CUN) also known as MT-TL2 is a transfer RNA which in humans is encoded by the mitochondrial MT-TL2 gene.

Mitochondrially encoded tRNA asparagine also known as MT-TN is a transfer RNA which in humans is encoded by the mitochondrial MT-TN gene.

Mitochondrially encoded tRNA arginine also known as MT-TR is a transfer RNA which in humans is encoded by the mitochondrial MT-TR gene.

COA3

Cytochrome c oxidase assembly factor 3, also known as Coiled-coil domain-containing protein 56, or Mitochondrial translation regulation assembly intermediate of cytochrome c oxidase protein of 12 kDa is a protein that in humans is encoded by the COA3 gene. This gene encodes a member of the cytochrome c oxidase assembly factor family. Studies of a related gene in fly suggest that the encoded protein is localized to mitochondria and is essential for cytochrome c oxidase function.

COX14

Cytochrome c oxidase assembly factor COX14 is a protein that in humans is encoded by the COX14 gene. This gene encodes a small single-pass transmembrane protein that localizes to mitochondria. This protein may play a role in coordinating the early steps of cytochrome c oxidase subunit assembly and, in particular, the synthesis and assembly of the COX I subunit of the holoenzyme. Mutations in this gene have been associated with mitochondrial complex IV deficiency. Alternative splicing results in multiple transcript variants.

References

  1. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000064358 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ Miki K, Sogabe S, Uno A, Ezoe T, Kasai N, Saeda M, Matsuura Y, Miki M (May 1994). "Application of an automatic molecular-replacement procedure to crystal structure analysis of cytochrome c2 from Rhodopseudomonas viridis". Acta Crystallographica Section D. 50 (Pt 3): 271–5. doi: 10.1107/S0907444993013952 . PMID   15299438.
  5. ↑ "Entrez Gene: COX3 cytochrome c oxidase subunit III".PD-icon.svgThis article incorporates text from this source, which is in the public domain.
  6. 1 2 3 Horváth R, Schoser BG, Müller-Höcker J, Völpel M, Jaksch M, Lochmüller H (December 2005). "Mutations in mtDNA-encoded cytochrome c oxidase subunit genes causing isolated myopathy or severe encephalomyopathy". Neuromuscular Disorders. 15 (12): 851–7. doi:10.1016/j.nmd.2005.09.005. PMID   16288875. S2CID   11683931.
  7. 1 2 3 4 5 6 "MT-CO3 - Cytochrome c oxidase subunit 3 - Homo sapiens (Human) - MT-CO3 gene & protein". www.uniprot.org. Retrieved 2018-08-21. CC-BY-icon-80x15.png  This article incorporates text available under the CC BY 4.0 license.
  8. 1 2 3 4 5 6 "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC   5210571 . PMID   27899622.
  9. ↑ Yao, Daniel. "Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information". amino.heartproteome.org. Archived from the original on 2018-08-22. Retrieved 2018-08-21.
  10. ↑ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC   4076475 . PMID   23965338.
  11. ↑ Michel H (November 1999). "Cytochrome c oxidase: catalytic cycle and mechanisms of proton pumping--a discussion". Biochemistry. 38 (46): 15129–40. doi:10.1021/bi9910934. PMID   10563795.
  12. ↑ Belevich I, Verkhovsky MI, Wikström M (April 2006). "Proton-coupled electron transfer drives the proton pump of cytochrome c oxidase". Nature. 440 (7085): 829–32. Bibcode:2006Natur.440..829B. doi:10.1038/nature04619. PMID   16598262. S2CID   4312050.
  13. ↑ Mather MW, Springer P, Hensel S, Buse G, Fee JA (March 1993). "Cytochrome oxidase genes from Thermus thermophilus. Nucleotide sequence of the fused gene and analysis of the deduced primary structures for subunits I and III of cytochrome caa3". The Journal of Biological Chemistry. 268 (8): 5395–408. doi: 10.1016/S0021-9258(18)53335-4 . PMID   8383670.
  14. ↑ Santana M, Kunst F, Hullo MF, Rapoport G, Danchin A, Glaser P (May 1992). "Molecular cloning, sequencing, and physiological characterization of the qox operon from Bacillus subtilis encoding the aa3-600 quinol oxidase". The Journal of Biological Chemistry. 267 (15): 10225–31. doi: 10.1016/S0021-9258(19)50007-2 . PMID   1316894.
  15. ↑ Chepuri V, Lemieux L, Au DC, Gennis RB (July 1990). "The sequence of the cyo operon indicates substantial structural similarities between the cytochrome o ubiquinol oxidase of Escherichia coli and the aa3-type family of cytochrome c oxidases". The Journal of Biological Chemistry. 265 (19): 11185–92. doi: 10.1016/S0021-9258(19)38574-6 . PMID   2162835.
  16. ↑ García-Horsman JA, Barquera B, Rumbley J, Ma J, Gennis RB (September 1994). "The superfamily of heme-copper respiratory oxidases". Journal of Bacteriology. 176 (18): 5587–600. doi:10.1128/jb.176.18.5587-5600.1994. PMC   196760 . PMID   8083153.
  17. ↑ Johns DR, Neufeld MJ (October 1993). "Cytochrome c oxidase mutations in Leber hereditary optic neuropathy". Biochemical and Biophysical Research Communications. 196 (2): 810–5. doi:10.1006/bbrc.1993.2321. PMID   8240356.
  18. ↑ Hanna MG, Nelson IP, Rahman S, Lane RJ, Land J, Heales S, Cooper MJ, Schapira AH, Morgan-Hughes JA, Wood NW (July 1998). "Cytochrome c oxidase deficiency associated with the first stop-codon point mutation in human mtDNA". American Journal of Human Genetics. 63 (1): 29–36. doi:10.1086/301910. PMC   1377234 . PMID   9634511.
  19. ↑ Keightley JA, Hoffbuhr KC, Burton MD, Salas VM, Johnston WS, Penn AM, Buist NR, Kennaway NG (April 1996). "A microdeletion in cytochrome c oxidase (COX) subunit III associated with COX deficiency and recurrent myoglobinuria". Nature Genetics. 12 (4): 410–6. doi:10.1038/ng0496-410. PMID   8630495. S2CID   13314201.
  20. ↑ "2 binary interactions found for search term COX3". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-08-21.

Further reading

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