Biology:Cytochrome c oxidase subunit III

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Short description: Enzyme of the respiratory chain encoded by the mitochondrial genome


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example
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.[1]
Identifiers
SymbolCOX3
PfamPF00510
InterProIPR000298
PROSITEPDOC50253
SCOP21occ / SCOPe / SUPFAM
TCDB3.D.4
OPM superfamily4
OPM protein1v55
CDDcd01665

Cytochrome c oxidase subunit III (COX3) is an enzyme that in humans is encoded by the MT-CO3 gene.[2] It is one of main transmembrane subunits of cytochrome c oxidase. It is also one of the three mitochondrial DNA (mtDNA) encoded subunits (MT-CO1, MT-CO2, MT-CO3) of respiratory complex IV. Variants of it have been associated with isolated myopathy, severe encephalomyopathy, Leber hereditary optic neuropathy, mitochondrial complex IV deficiency, and recurrent myoglobinuria .[3][4][5]

Structure

The MT-CO3 gene produces a 30 kDa protein composed of 261 amino acids.[6][7] 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.[4][5]

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 [math]\displaystyle{ \rightleftharpoons }[/math] 4 cytochrome c+3 + 2 H2O

This reaction is coupled to the pumping of four additional protons across the mitochondrial or bacterial membrane.[8][9]

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.[10]

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.[11][12][13]

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 .[3][4][5]

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.[14][4][5]

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.[3][15][4][5]

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.[16][4][5]

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.[17]

References

  1. ↑ "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. May 1994. doi:10.1107/S0907444993013952. PMID 15299438. Bibcode: 1994AcCrD..50..271M. 
  2. ↑ "Entrez Gene: COX3 cytochrome c oxidase subunit III". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4514.  This article incorporates text from this source, which is in the public domain.
  3. ↑ 3.0 3.1 3.2 "Mutations in mtDNA-encoded cytochrome c oxidase subunit genes causing isolated myopathy or severe encephalomyopathy". Neuromuscular Disorders 15 (12): 851–7. December 2005. doi:10.1016/j.nmd.2005.09.005. PMID 16288875. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 "MT-CO3 - Cytochrome c oxidase subunit 3 - Homo sapiens (Human) - MT-CO3 gene & protein" (in en). https://www.uniprot.org/uniprot/P00414.  This article incorporates text available under the CC BY 4.0 license.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "UniProt: the universal protein knowledgebase". Nucleic Acids Research 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMID 27899622. 
  6. ↑ Yao, Daniel. "Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information". https://amino.heartproteome.org/web/protein/P00414. 
  7. ↑ "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. October 2013. doi:10.1161/CIRCRESAHA.113.301151. PMID 23965338. 
  8. ↑ "Cytochrome c oxidase: catalytic cycle and mechanisms of proton pumping--a discussion". Biochemistry 38 (46): 15129–40. November 1999. doi:10.1021/bi9910934. PMID 10563795. 
  9. ↑ "Proton-coupled electron transfer drives the proton pump of cytochrome c oxidase". Nature 440 (7085): 829–32. April 2006. doi:10.1038/nature04619. PMID 16598262. Bibcode: 2006Natur.440..829B. 
  10. ↑ "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. March 1993. doi:10.1016/S0021-9258(18)53335-4. PMID 8383670. 
  11. ↑ "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. May 1992. doi:10.1016/S0021-9258(19)50007-2. PMID 1316894. 
  12. ↑ "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. July 1990. doi:10.1016/S0021-9258(19)38574-6. PMID 2162835. 
  13. ↑ "The superfamily of heme-copper respiratory oxidases". Journal of Bacteriology 176 (18): 5587–600. September 1994. doi:10.1128/jb.176.18.5587-5600.1994. PMID 8083153. 
  14. ↑ "Cytochrome c oxidase mutations in Leber hereditary optic neuropathy". Biochemical and Biophysical Research Communications 196 (2): 810–5. October 1993. doi:10.1006/bbrc.1993.2321. PMID 8240356. 
  15. ↑ "Cytochrome c oxidase deficiency associated with the first stop-codon point mutation in human mtDNA". American Journal of Human Genetics 63 (1): 29–36. July 1998. doi:10.1086/301910. PMID 9634511. 
  16. ↑ "A microdeletion in cytochrome c oxidase (COX) subunit III associated with COX deficiency and recurrent myoglobinuria". Nature Genetics 12 (4): 410–6. April 1996. doi:10.1038/ng0496-410. PMID 8630495. 
  17. ↑ "2 binary interactions found for search term COX3". IntAct Molecular Interaction Database. EMBL-EBI. https://www.ebi.ac.uk/intact/interactions?conversationContext=3&query=COX3. 

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.




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