Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1) is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that in humans is encoded by the ''COX4I1''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. COX4I1 is a nuclear-encoded

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

cytochrome c oxidase The enzyme cytochrome c oxidase or Complex IV (was , now reclassified as a translocasEC 7.1.1.9 is a large transmembrane protein complex found in bacteria, archaea, and the mitochondria of eukaryotes. It is the last enzyme in the Cellular respir ...

(COX) subunit 4. Cytochrome c oxidase (

complex IV The enzyme cytochrome c oxidase or Complex IV (was , now reclassified as a translocasEC 7.1.1.9 is a large transmembrane protein complex found in bacteria, archaea, and the mitochondria of eukaryotes. It is the last enzyme in the respiratory ele ...

) is a multi-subunit enzyme complex that couples the transfer of

electron The electron (, or in nuclear reactions) is a subatomic particle with a negative one elementary charge, elementary electric charge. It is a fundamental particle that comprises the ordinary matter that makes up the universe, along with up qua ...

s from cytochrome c to molecular

oxygen Oxygen is a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...

and contributes to a

proton A proton is a stable subatomic particle, symbol , Hydron (chemistry), H+, or 1H+ with a positive electric charge of +1 ''e'' (elementary charge). Its mass is slightly less than the mass of a neutron and approximately times the mass of an e ...

electrochemical gradient An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane. The gradient consists of two parts: * The chemical gradient, or difference in Concentration, solute concentration across ...

across the

inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...

, acting as the terminal enzyme of the

mitochondrial A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

respiratory chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples this ...

Antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...

against COX4 can be used to identify the inner membrane of

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

immunofluorescence Immunofluorescence (IF) is a light microscopy-based technique that allows detection and localization of a wide variety of target biomolecules within a cell or tissue at a quantitative level. The technique utilizes the binding specificity of anti ...

studies. Mutations in COX4I1 have been associated with COX deficiency and

Fanconi anemia Fanconi anemia (FA) is a rare, autosomal recessive genetic disease characterized by aplastic anemia, congenital defects, endocrinological abnormalities, and an increased incidence of developing cancer. The study of Fanconi anemia has improve ...

Structure

''COX4I1'' is located on the

q arm In genetics, a locus (: loci) is a specific, fixed position on a chromosome where a particular gene or genetic marker is located. Each chromosome carries many genes, with each gene occupying a different position or locus; in humans, the total numb ...

chromosome 16 Chromosome 16 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 16 spans about 90 million base pairs (the building material of DNA) and represents just under 3% of the total DNA in cel ...

in position 24.1 and has 6

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

s. The ''COX4I1'' gene produces a 9.3 kDa

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

composed of 83

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s. ''COX4I1'' is expressed ubiquitously. The protein encoded by ''COX4I1'' belongs to the cytochrome c oxidase IV family. COX4I1 has a

transit peptide A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16–30 amino acids long) present at the N-t ...

domain and

acetyl In organic chemistry, an acetyl group is a functional group denoted by the chemical formula and the structure . It is sometimes represented by the symbol Ac (not to be confused with the element actinium). In IUPAC nomenclature, an acetyl grou ...

and

phosphoprotein A phosphoprotein is a protein that is posttranslationally modified by the attachment of either a single phosphate group, or a complex molecule such as 5'-phospho-DNA, through a phosphate group. The target amino acid is most often serine, threonin ...

modifications. 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

and is an isoform of the nuclear-encoded subunit IV of

(complex IV), the terminal

oxidase In biochemistry, an oxidase is an oxidoreductase (any enzyme that catalyzes a redox reaction) that uses dioxygen (O2) as the electron acceptor. In reactions involving donation of a hydrogen atom, oxygen is reduced to water (H2O) or hydrogen peroxid ...

in mitochondrial electron transport. Complex IV is a multi-subunit enzyme complex that couples the transfer of

s from cytochrome c to molecular

and contributes to a

across the

. 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.

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

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...

s. Among these, COX deficiency and

have been suspected and linked to mutations in the ''COX4I1'' gene. Clinical features of pathogenic variants of ''COX4I1'' can include

short stature Short stature refers to a height of a human which is below typical. Whether a person is considered short depends on the context. Because of the lack of preciseness, there is often disagreement about the degree of shortness that should be called ...

, poor weight gain, mild

dysmorphic feature A dysmorphic feature is an abnormal difference in body structure. It can be an isolated finding in an otherwise normal individual, or it can be related to a congenital disorder, genetic syndrome or birth defect. Dysmorphology is the study of dysm ...

mental retardation Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...

spastic paraplegia Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive Gait abnormality, gait disorder. The disease presents with progressive stiffness (spasticity) and contraction in the lower limbs. HSP is als ...

, severe

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

, a narrow and arched

palate The palate () is the roof of the mouth in humans and other mammals. It separates the oral cavity from the nasal cavity. A similar structure is found in crocodilians, but in most other tetrapods, the oral and nasal cavities are not truly sep ...

, malar hypoplasia, little

subcutaneous fat The subcutaneous tissue (), also called the hypodermis, hypoderm (), subcutis, or superficial fascia, is the lowermost layer of the integumentary system in vertebrates. The types of cells found in the layer are fibroblasts, adipose cells, and ...

, and

arachnodactyly Arachnodactyly ("spider fingers") is a medical condition that is characterized by fingers and toes that are abnormally long and slender, in comparison to the palm of the hand and arch of the foot. In some cases, the thumbs of an individual with the ...

. The homozygous

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

K101N and a de novo 16q24.1 interstitial duplication have been found to cause defective COX4I1.

Interactions

COX4I1 has 153 protein-protein interactions with 142 of them being co-complex interactions. COX4I1 has been found to interact with

SDCBP Syntenin-1 is a protein that in humans is encoded by the ''SDCBP'' gene. Function The protein encoded by this gene was initially identified as a molecule linking syndecan-mediated signaling to the cytoskeleton. The syntenin protein contains t ...

MT-CO1 Cytochrome c oxidase I (COX1) also known as mitochondrially encoded cytochrome c oxidase I (MT-CO1) is a protein that is encoded by the ''MT-CO1'' gene in eukaryotes. The gene is also called ''COX1'', ''CO1'', or ''COI''. Cytochrome c oxidase ...

IKBKE Inhibitor of nuclear factor kappa-B kinase subunit epsilon also known as I-kappa-B kinase epsilon or IKK-epsilon is an enzyme that in humans is encoded by the ''IKBKE'' gene. Interactions IKBKE has been shown to interact with TANK. Function ...

, TMBIM4, and

MCL1 Induced myeloid leukemia cell differentiation protein Mcl-1 is a protein that in humans is encoded by the ''MCL1'' gene. Function The protein encoded by this gene belongs to the Bcl-2 family. Alternative splicing occurs at this locus and two t ...

LON Lon or LON may refer to: People * Lon (photographer), pseudonym of Alonzo Hanagan, also known as "Lon of New York" * Lon (name), a list of people with the given name, nickname or surname Fictional characters * Nero Wolfe supporting characters#Lon ...

, a mitochondrial

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...

, has also been suggested to regulate the COX4 subunit isoforms by degrading COX4I1 under

hypoxic Hypoxia means a lower than normal level of oxygen, and may refer to: Reduced or insufficient oxygen * Hypoxia (environmental), abnormally low oxygen content of a specific environment ** Hypoxia in fish, responses of fish to hypoxia * Hypoxia (medi ...

conditions.

Structure

Function

Clinical Significance

Interactions

References

External links

Further reading