COX4I1

Last updated
COX4I1
Identifiers
Aliases COX4I1 , COX4, COX4-1, COXIV, COX IV-1, COXIV-1, cytochrome c oxidase subunit 4I1, MC4DN16
External IDs OMIM: 123864 MGI: 88473 HomoloGene: 37537 GeneCards: COX4I1
Orthologs
SpeciesHumanMouse
Entrez

1327

12857

Ensembl

ENSG00000131143

ENSMUSG00000031818

UniProt

P13073
Q86WV2

P19783

RefSeq (mRNA)

NM_001293559
NM_009941

RefSeq (protein)

NP_001280488
NP_034071

Location (UCSC) Chr 16: 85.8 – 85.81 Mb Chr 8: 121.39 – 121.4 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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 (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. [5] [6] [7] Antibodies against COX4 can be used to identify the inner membrane of mitochondria in immunofluorescence studies. [8] Mutations in COX4I1 have been associated with COX deficiency and Fanconi anemia. [9] [10]

Contents

Structure

COX4I1 is located on the q arm of chromosome 16 in position 24.1 and has 6 exons. [5] The COX4I1 gene produces a 9.3 kDa protein composed of 83 amino acids. [11] [12] COX4I1 is expressed ubiquitously. The protein encoded by COX4I1 belongs to the cytochrome c oxidase IV family. COX4I1 has a transit peptide domain and acetyl and phosphoprotein amino acid modifications. [13] [14] It is located at the 3' of the NOC4 (neighbor of COX4) gene in a head-to-head orientation, and shares a promoter with it. [5]

Function

COX4I1 encodes a protein that is located in the inner mitochondrial membrane and is an isoform of the nuclear-encoded subunit IV of cytochrome c oxidase (complex IV), the terminal oxidase in mitochondrial electron transport. 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. [5] The expression of COX4I1, along with COX4I2, may be regulated by oxygen levels, with reduced levels of oxygen leading to increased COX4I2 expression and COX4I1 degradation. This suggests a role for COX4I1 in the optimization of the electron transfer chain under different conditions. [15]

Clinical Significance

Although relatively little is known about the function of COX4I1, mutations in this gene have been associated with mitochondrial complex IV diseases with severe phenotypes. Among these, COX deficiency and Fanconi anemia have been suspected and linked to mutations in the COX4I1 gene. Clinical features of pathogenic variants of COX4I1 can include short stature, poor weight gain, mild dysmorphic features, mental retardation, spastic paraplegia, severe epilepsy, a narrow and arched palate, malar hypoplasia, little subcutaneous fat, and arachnodactyly. The homozygous mutation K101N and a de novo 16q24.1 interstitial duplication have been found to cause defective COX4I1. [9] [10]

Interactions

COX4I1 has 153 protein-protein interactions with 142 of them being co-complex interactions. COX4I1 has been found to interact with SDCBP, MT-CO1, IKBKE, TMBIM4, and MCL1. [16] 

 LON, a mitochondrial protease, has also been suggested to regulate the COX4 subunit isoforms by degrading COX4I1 under hypoxic conditions. [15]

Related Research Articles

<span class="mw-page-title-main">Cytochrome c oxidase</span> Complex enzyme found in bacteria, archaea, and mitochondria of eukaryotes

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

<span class="mw-page-title-main">Cytochrome c oxidase subunit I</span> 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.

<span class="mw-page-title-main">Cytochrome c oxidase subunit 2</span> 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.

<span class="mw-page-title-main">Cytochrome c oxidase subunit III</span> 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. It is also one of the three mitochondrial DNA (mtDNA) encoded subunits 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.

<span class="mw-page-title-main">SCO2</span>

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.

<span class="mw-page-title-main">COX4I2</span> Protein-coding gene in the species Homo sapiens

Cytochrome c oxidase subunit 4 isoform 2, mitochondrial is an enzyme that in humans is encoded by the COX4I2 gene. COX4I2 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. Mutations in COX4I2 have been associated with exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis (EPIDACH).

<span class="mw-page-title-main">COX6B1</span> Protein-coding gene in the species Homo sapiens

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).

<span class="mw-page-title-main">COX7A2</span>

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

<span class="mw-page-title-main">COX10</span> Mammalian protein found in Homo sapiens

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.

<span class="mw-page-title-main">COX5B</span>

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.

<span class="mw-page-title-main">COX6A1</span>

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.

<span class="mw-page-title-main">COX7A1</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">COX7B</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">COX5A</span>

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.

<span class="mw-page-title-main">COX6A2</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">COX6B2</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">COX8A</span>

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.

<span class="mw-page-title-main">COX14</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">COA6</span> Protein-coding gene in the species Homo sapiens

Cytochrome c oxidase assembly factor 6 is a protein that in humans is encoded by the COA6 gene. Mitochondrial respiratory chain Complex IV, or cytochrome c oxidase, is the component of the respiratory chain that catalyzes the transfer of electrons from intermembrane space cytochrome c to molecular oxygen in the matrix and as a consequence contributes to the proton gradient involved in mitochondrial ATP synthesis. The COA6 gene encodes an assembly factor for mitochondrial complex IV and is a member of the cytochrome c oxidase subunit 6B family. This protein is located in the intermembrane space, associating with SCO2 and COX2. It stabilizes newly formed COX2 and is part of the mitochondrial copper relay system. Mutations in this gene result in fatal infantile cardioencephalomyopathy.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000131143 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000031818 - 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. 1 2 3 4 "Entrez Gene: COX4I1 cytochrome c oxidase subunit IV isoform 1".PD-icon.svg This article incorporates text from this source, which is in the public domain .
  6. ↑ Zeviani M, Nakagawa M, Herbert J, Lomax MI, Grossman LI, Sherbany AA, Miranda AF, DiMauro S, Schon EA (Dec 1987). "Isolation of a cDNA clone encoding subunit IV of human cytochrome c oxidase". Gene. 55 (2–3): 205–17. doi:10.1016/0378-1119(87)90281-2. PMID   2444497.
  7. ↑ Lomax MI, Welch MD, Darras BT, Francke U, Grossman LI (February 1990). "Novel use of a chimpanzee pseudogene for chromosomal mapping of human cytochrome c oxidase subunit IV". Gene. 86 (2): 209–16. doi:10.1016/0378-1119(90)90281-U. PMID   2157630.
  8. ↑ "Anti-COX4 antibody (GTX101499) | GeneTex".
  9. 1 2 Abu-Libdeh B, Douiev L, Amro S, Shahrour M, Ta-Shma A, Miller C, Elpeleg O, Saada A (October 2017). "Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia". European Journal of Human Genetics. 25 (10): 1142–1146. doi:10.1038/ejhg.2017.112. PMC   5602013 . PMID   28766551.
  10. 1 2 Quéméner-Redon S, Bénech C, Audebert-Bellanger S, Friocourt G, Planes M, Parent P, Férec C (April 2013). "A small de novo 16q24.1 duplication in a woman with severe clinical features" (PDF). European Journal of Medical Genetics. 56 (4): 211–5. doi:10.1016/j.ejmg.2013.01.001. PMID   23333879.
  11. ↑ Yao, Daniel. "Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information". amino.heartproteome.org. Archived from the original on 2018-08-04. Retrieved 2018-08-03.
  12. ↑ 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.
  13. ↑ "COX4I1 - Cytochrome c oxidase subunit 4 isoform 1, mitochondrial precursor - Homo sapiens (Human) - COX4I1 gene & protein". uniprot.org. Retrieved 2018-08-03. CC BY icon-80x15.png  This article incorporates text available under the CC BY 4.0 license.
  14. ↑ "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC   5210571 . PMID   27899622.
  15. 1 2 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.
  16. ↑ "153 binary interactions found for search term COX4I1". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-08-25.

Further reading

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