COX4I1

{{Short description|Protein-coding gene in the species Homo sapiens}}

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.{{cite web|url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1327|title=Entrez Gene: COX4I1 cytochrome c oxidase subunit IV isoform 1}}{{PD-notice}}{{cite journal | vauthors = Zeviani M, Nakagawa M, Herbert J, Lomax MI, Grossman LI, Sherbany AA, Miranda AF, DiMauro S, Schon EA | title = Isolation of a cDNA clone encoding subunit IV of human cytochrome c oxidase | journal = Gene | volume = 55 | issue = 2–3 | pages = 205–17 | date = Dec 1987 | pmid = 2444497 | doi = 10.1016/0378-1119(87)90281-2 }}{{cite journal | vauthors = Lomax MI, Welch MD, Darras BT, Francke U, Grossman LI | title = Novel use of a chimpanzee pseudogene for chromosomal mapping of human cytochrome c oxidase subunit IV | journal = Gene | volume = 86 | issue = 2 | pages = 209–16 | date = February 1990 | pmid = 2157630 | doi = 10.1016/0378-1119(90)90281-U }} Antibodies against COX4 can be used to identify the inner membrane of mitochondria in immunofluorescence studies.{{Cite web|url=https://www.genetex.com/Product/Detail/COX4-antibody/GTX101499|title = Anti-COX4 antibody (GTX101499) | GeneTex}} Mutations in COX4I1 have been associated with COX deficiency and Fanconi anemia.

Structure

COX4I1 is located on the q arm of chromosome 16 in position 24.1 and has 6 exons. The COX4I1 gene produces a 9.3 kDa protein composed of 83 amino acids.{{Cite web|url=https://amino.heartproteome.org/web/protein/Q86WV2|title=Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) —— Protein Information|last=Yao|first=Daniel|website=amino.heartproteome.org|access-date=2018-08-03|archive-url=https://web.archive.org/web/20180804075718/https://amino.heartproteome.org/web/protein/Q86WV2|archive-date=2018-08-04|url-status=dead}}{{cite journal | vauthors = 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 | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = October 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }} 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.{{Cite web|url=https://www.uniprot.org/uniprot/P13073|title=COX4I1 - Cytochrome c oxidase subunit 4 isoform 1, mitochondrial precursor - Homo sapiens (Human) - COX4I1 gene & protein|website=uniprot.org|language=en|access-date=2018-08-03}}{{CC-notice|cc=by4}}{{cite journal | title = UniProt: the universal protein knowledgebase | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D158–D169 | date = January 2017 | pmid = 27899622 | pmc = 5210571 | doi = 10.1093/nar/gkw1099 }} 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.

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. 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.{{cite journal | vauthors = Fukuda R, Zhang H, Kim JW, Shimoda L, Dang CV, Semenza GL | title = HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells | journal = Cell | volume = 129 | issue = 1 | pages = 111–22 | date = April 2007 | pmid = 17418790 | doi = 10.1016/j.cell.2007.01.047 | s2cid = 2331820 | doi-access = free }}

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.{{cite journal | vauthors = Abu-Libdeh B, Douiev L, Amro S, Shahrour M, Ta-Shma A, Miller C, Elpeleg O, Saada A | title = Mutation in the COX4I1 gene is associated with short stature, poor weight gain and increased chromosomal breaks, simulating Fanconi anemia | journal = European Journal of Human Genetics | volume = 25 | issue = 10 | pages = 1142–1146 | date = October 2017 | pmid = 28766551 | pmc = 5602013 | doi = 10.1038/ejhg.2017.112 }}{{cite journal | vauthors = Quéméner-Redon S, Bénech C, Audebert-Bellanger S, Friocourt G, Planes M, Parent P, Férec C | title = A small de novo 16q24.1 duplication in a woman with severe clinical features | journal = European Journal of Medical Genetics | volume = 56 | issue = 4 | pages = 211–5 | date = April 2013 | pmid = 23333879 | doi = 10.1016/j.ejmg.2013.01.001 | url = http://www.hal.inserm.fr/inserm-00788405/file/Redon_et_al.pdf }}

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.{{cite web | url = https://www.ebi.ac.uk/intact/interactions?conversationContext=3&query=COX4I1 | title = 153 binary interactions found for search term COX4I1 | work = IntAct Molecular Interaction Database | publisher = EMBL-EBI | access-date = 2018-08-25 }}

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

References

External links

{{UCSC gene info|COX4I1}}