COX4I2

Last updated
COX4I2
Identifiers
Aliases COX4I2 , COX4, COX4-2, COX4B, COX4L2, COXIV-2, dJ857M17.2, cytochrome c oxidase subunit 4I2
External IDs OMIM: 607976 MGI: 2135755 HomoloGene: 13082 GeneCards: COX4I2
Orthologs
SpeciesHumanMouse
Entrez

84701

84682

Ensembl

ENSG00000131055

ENSMUSG00000009876

UniProt

Q96KJ9

Q91W29

RefSeq (mRNA)

NM_032609

NM_053091

RefSeq (protein)

NP_115998

NP_444321

Location (UCSC) Chr 20: 31.64 – 31.65 Mb Chr 2: 152.75 – 152.77 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Cytochrome c oxidase subunit 4 isoform 2, mitochondrial is an enzyme that in humans is encoded by the COX4I2 gene. [5] [6] COX4I2 is a nuclear-encoded isoform of cytochrome c oxidase (COX) subunit 4. Cytochrome c oxidase (complex IV) 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. Mutations in COX4I2 have been associated with exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis (EPIDACH). [7] [8]

Contents

Structure

COX4I2 is located on the q arm of chromosome 20 in position 11.21 and has 6 exons. [7] The COX4I2 gene produces a 20 kDa protein composed of 171 amino acids. [9] [10] The protein encoded by COX4I2 belongs to the cytochrome c oxidase IV family. COX4I2 has a transit peptide domain and a disulfide bond amino acid modification. [11] [12] A Glu138 residue, which corresponds to a Glu136 residue in COX4I1, is believed to be highly conserved and structurally important for the mitochondrial COX response to hypoxia. [8]

Function

Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It 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 be involved in the regulation and assembly of the complex. The COX4I2 nuclear gene encodes isoform 2 of subunit IV. Isoform 1 of subunit IV is encoded by a different gene, however, the two genes show a similar structural organization. Subunit IV is the largest nuclear encoded subunit which plays a pivotal role in COX regulation. It is located on the inner mitochondrial membrane on the matrix side. Expression of COX4I2 is highest in the placenta and the lungs. [7] [11] [12] Additionally, the expression of COX4I2, along with COX4I1 , may be regulated by oxygen levels, with reduced levels of oxygen leading to increased COX4I2 expression and COX4I1 degradation. This suggests a role for COX4I2 in the optimization of the electron transfer chain under different conditions. [13]

Clinical Significance

Mutations in COX4I2 have been associated with exocrine pancreatic insufficiency, dyserythropoeitic anemia, and calvarial hyperostosis (EPIDACH). Characteristics of this disease include pancreatic insufficiency, intestinal malabsorption, failure to thrive, and anemia soon after birth. Additional symptoms have included steatorrhea, splenomegaly and hepatomegaly, pancreatic atrophy, generalized muscle hypotonia, hyperostosis, yellowish sclera associated with mild indirect hyperbilirubinemia, impaired coagulation functions, elevated LDH, alanine, and bilirubin, and reduced vitamin E levels. A homozygous mutation, E138K, has been found to result in reduced COX4I2 expression (25% in fibroblasts) and an impaired response to hypoxia. Functional COX4I2 expression below 40% of its normal level is predicted to be rate-limiting, with the E138K mutation occurring in what is believed to be a highly conserved residue of subunit IV. [11] [12] [8]

Interactions

COX4I2 has been shown to interact with Cytochrome c (CYCS). [14] [15] [16] [17] Additionally, APP, COA3, and KRAS have been found to have protein-protein interactions with COX4I2. [18]

Related Research Articles

Cytochrome c oxidase

The enzyme cytochrome c oxidase or Complex IV, EC 1.9.3.1, is a large transmembrane protein complex found in bacteria, archaea, and the mitochondria of eukaryotes.

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.

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

Cytochrome c oxidase subunit III (COX3) is an enzyme that in humans is encoded by the MT-CO3 gene. 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 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.

SCO2

SCO2 cytochrome c oxidase assembly is a protein that in humans is encoded by the SCO2 gene. The encoded protein is one of the cytochrome c oxidase (COX)(Complex IV) assembly factors. Human COX is a multimeric protein complex that requires several assembly factors. Cytochrome c oxidase (COX) catalyzes the transfer of electrons from cytochrome c to molecular oxygen, which helps to maintain the proton gradient across the inner mitochondrial membrane that is necessary for aerobic ATP production. The encoded protein is a metallochaperone that is involved in the biogenesis of cytochrome c oxidase subunit II. Mutations in this gene are associated with fatal infantile encephalocardiomyopathy and myopia 6.

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).

COX7A2

Cytochrome c oxidase polypeptide 7A2, mitochondrial is an enzyme that in humans is encoded by the COX7A2 gene.

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.

COX5B

Cytochrome c oxidase subunit 5B, mitochondrial is an enzyme in humans that is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain. In humans, cytochrome c oxidase subunit 5B is encoded by the COX5B gene.

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.

COX7A1

Cytochrome c oxidase polypeptide 7A1, mitochondrial is an enzyme that in humans is encoded by the COX7A1 gene.

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.

COX5A

Cytochrome c oxidase subunit 5a is a protein that in humans is encoded by the COX5A gene. Cytochrome c oxidase 5A is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain.

COX6A2

Cytochrome c oxidase subunit VIa polypeptide 2 is a protein that in humans is encoded by the COX6A2 gene. Cytochrome c oxidase 6A2 is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain.

COX6B2

Cytochrome c oxidase subunit VIb polypeptide 2 is a protein that in humans is encoded by the COX6B2 gene. Cytochrome c oxidase 6B2 is a subunit of the cytochrome c oxidase complex, also known as Complex IV, the last enzyme in the mitochondrial electron transport chain.

COX8A

Cytochrome c oxidase subunit 8A (COX8A) is a protein that in humans is encoded by the COX8A gene. Cytochrome c oxidase 8A is a subunit of the cytochrome c oxidase complex, also known as Complex IV. Mutations in the COX8A gene have been associated with complex IV deficiency with Leigh syndrome and epilepsy.

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.

Cytochrome c oxidase assembly factor COX20 is a protein that in humans is encoded by the COX20 gene. This gene encodes a protein that plays a role in the assembly of cytochrome c oxidase, an important component of the respiratory pathway. Mutations in this gene can cause mitochondrial complex IV deficiency. There are multiple pseudogenes for this gene. Alternative splicing results in multiple transcript variants.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000131055 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000009876 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Hüttemann M, Kadenbach B, Grossman LI (April 2001). "Mammalian subunit IV isoforms of cytochrome c oxidase". Gene. 267 (1): 111–23. doi:10.1016/S0378-1119(01)00385-7. PMID   11311561.
  6. ↑ Hüttemann M, Lee I, Liu J, Grossman LI (November 2007). "Transcription of mammalian cytochrome c oxidase subunit IV-2 is controlled by a novel conserved oxygen responsive element". The FEBS Journal. 274 (21): 5737–48. doi: 10.1111/j.1742-4658.2007.06093.x . PMID   17937768. S2CID   46455551.
  7. 1 2 3 "Entrez Gene: COX4I2 cytochrome c oxidase subunit IV isoform 2 (lung)".PD-icon.svgThis article incorporates text from this source, which is in the public domain.
  8. 1 2 3 Shteyer E, Saada A, Shaag A, Al-Hijawi FA, Kidess R, Revel-Vilk S, Elpeleg O (March 2009). "Exocrine pancreatic insufficiency, dyserythropoeitic anemia, and calvarial hyperostosis are caused by a mutation in the COX4I2 gene". American Journal of Human Genetics. 84 (3): 412–7. doi:10.1016/j.ajhg.2009.02.006. PMC   2668012 . PMID   19268275.
  9. ↑ 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.
  10. ↑ Yao, Daniel. "Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information". amino.heartproteome.org. Archived from the original on 2018-08-07. Retrieved 2018-08-06.
  11. 1 2 3 "COX4I2 - Cytochrome c oxidase subunit 4 isoform 2, mitochondrial precursor - Homo sapiens (Human) - COX4I2 gene & protein". www.uniprot.org. Retrieved 2018-08-06. CC-BY-icon-80x15.png  This article incorporates text available under the CC BY 4.0 license.
  12. 1 2 3 "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC   5210571 . PMID   27899622.
  13. ↑ Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL (April 2007). "HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells". Cell. 129 (1): 111–22. doi: 10.1016/j.cell.2007.01.047 . PMID   17418790. S2CID   2331820.
  14. ↑ Michel B, Bosshard HR (August 1984). "Spectroscopic analysis of the interaction between cytochrome c and cytochrome c oxidase". The Journal of Biological Chemistry. 259 (16): 10085–91. doi: 10.1016/S0021-9258(18)90932-4 . PMID   6088481.
  15. ↑ Wiedemann FR, Vielhaber S, Schröder R, Elger CE, Kunz WS (March 2000). "Evaluation of methods for the determination of mitochondrial respiratory chain enzyme activities in human skeletal muscle samples". Analytical Biochemistry. 279 (1): 55–60. doi:10.1006/abio.1999.4434. PMID   10683230.
  16. ↑ Sampson V, Alleyne T (December 2001). "Cytochrome c/cytochrome c oxidase interaction. Direct structural evidence for conformational changes during enzyme turnover". European Journal of Biochemistry. 268 (24): 6534–44. doi: 10.1046/j.0014-2956.2001.02608.x . PMID   11737208.
  17. ↑ Lynch SR, Sherman D, Copeland RA (January 1992). "Cytochrome c binding affects the conformation of cytochrome a in cytochrome c oxidase". The Journal of Biological Chemistry. 267 (1): 298–302. doi: 10.1016/S0021-9258(18)48493-1 . PMID   1309738.
  18. ↑ Lab, Mike Tyers. "COX4I2 Result Summary | BioGRID". thebiogrid.org. Retrieved 2018-08-06.

Further reading

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