Cytochrome c oxidase assembly protein COX15 homolog (COX15), also known as heme A synthase, is a

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 ...

that in humans is encoded by the ''COX15''

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 ...

. This protein localizes to 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 ...

and involved in

heme A Heme A (or haem A) is a heme, a coordination complex consisting of a macrocyclic ligand called a porphyrin, chelating an iron atom. Heme A is a biomolecule and is produced naturally by many organisms. Heme A, often appears a dichroic green/red whe ...

biosynthesis. COX15 is also part of a three-component mono-oxygenase (

ferredoxin Ferredoxins (from Latin ''ferrum'': iron + redox, often abbreviated "fd") are iron–sulfur proteins that mediate electron transfer in a range of metabolic reactions. The term "ferredoxin" was coined by D.C. Wharton of the DuPont Co. and applied t ...

, ferredoxin reductase, and COX15) that catalyses the hydroxylation of the

methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated a ...

at position eight of the protoheme molecule.

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, ...

s in this gene has been reported in patients with hypertrophic

cardiomyopathy Cardiomyopathy is a group of primary diseases of the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. A ...

as well as

Leigh syndrome Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who fir ...

, and characterized by delayed onset of symptoms,

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but it is a potential manifestation of many different dis ...

, feeding difficulties, failure to thrive, motor regression, and

brain stem The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is co ...

signs.

Structure

Gene

The ''COX15'' gene lies on the chromosome location of 10q24 and consists of nine exons. Two splice variants formed by

alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

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 ...

9, COX15.1 and COX15.2, differ in the

C-terminal domain The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

of the protein and the 39- UTR of the transcript. But the functional significance of the different

isoforms 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 ...

is still unknown.

Protein

The COX15 protein localizes to the inner mitochondrial membrane and has several predicted

transmembrane domains A transmembrane domain (TMD, TM domain) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in ...

. Four conserved histidine residues are proven to be critical for COX15 activity. Both COX15 multimerization and enzymatic activity would be impaired if the 20-residue linker region connecting the two conserved domains of COX15 is removed.

Function

COX15 is one of the cytochrome c oxidase (

COX Cox or COX may refer to: Companies * Cox Enterprises, a media and communications company ** Cox Communications, cable provider ** Cox Media Group, a company that owns television and radio stations ** Cox Automotive, an Atlanta-based busines ...

) assembly factors identified in

yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom (biology), kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are est ...

, playing a key role in the biosynthetic pathway of mitochondrial heme A, the prosthetic group of

cytochrome Cytochromes are redox-active proteins containing a heme, with a central iron (Fe) atom at its core, as a cofactor. They are involved in the electron transport chain and redox catalysis. They are classified according to the type of heme and its ...

a and a3. COX15 in yeast mediates hydroxylation of the methyl group at the C-8 position of the heme O molecule to form heme A. A deletion of COX15 results in undetectable levels of heme A but detectable levels of heme O. Similar findings are observed in patients with ''COX15'' deletion mutants, suggesting a similar functional role for COX15 in mammalian mitochondria and a similar pathogenesis for the COX deficiency. In

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 ...

of the respiratory chain, heme A is required for the proper folding of the Cox 1 subunit and subsequent assembly. A deficiency in the formation of heme A and functional COX would lead to impaired

electron transport 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 ...

and

oxidative phosphorylation Oxidative phosphorylation(UK , US : or electron transport-linked phosphorylation or terminal oxidation, is the metabolic pathway in which Cell (biology), cells use enzymes to Redox, oxidize nutrients, thereby releasing chemical energy in order ...

. COX15 multimerization is important for heme A biosynthesis and/or transfer to maturing COX.

Clinical significance

COX deficiency is one of the most frequent causes of

electron transport 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 th ...

defects in humans. Therefore, in highly energy-demanding organs and tissues, such as brain and retinal tissue, with mutations in ''COX15'', different clinical phenotypes are presented, such as early onset, fatal

hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM, or HOCM when obstructive) is a condition in which muscle tissues of the heart become thickened without an obvious cause. The parts of the heart most commonly affected are the interventricular septum and the ...

, and

encephalopathy Encephalopathy (; ) means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of overall brain dysfunction; this syndrome ...

. Signs and symptoms of these diseases that can manifest include

lactic acidosis Lactic acidosis refers to the process leading to the production of lactate by anaerobic metabolism. It increases hydrogen ion concentration tending to the state of acidemia or low pH. The result can be detected with high levels of lactate and lo ...

ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...

seizures A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

respiratory distress Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that c ...

psychomotor retardation Psychomotor retardation involves a slowing down of thought and a reduction of physical movements in an individual. It can cause a visible slowing of physical and emotional reactions, including speech and affect. Psychomotor retardation is most ...

vision loss Visual or vision impairment (VI or VIP) is the partial or total inability of visual perception. In the absence of treatment such as corrective eyewear, assistive devices, and medical treatment, visual impairment may cause the individual difficul ...

, eye movement abnormalities,

dysphagia Dysphagia is difficulty in swallowing. Although classified under " symptoms and signs" in ICD-10, in some contexts it is classified as a condition in its own right. It may be a sensation that suggests difficulty in the passage of solids or l ...

, and

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

lesions A lesion is any damage or abnormal change in the tissue of an organism, usually caused by injury or diseases. The term ''Lesion'' is derived from the Latin meaning "injury". Lesions may occur in both plants and animals. Types There is no de ...

. A sequence variation in COX15 has also been reported to associate with determining the genetic risk for

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

development.

Interactions

COX15 associates with Shy1 in distinct complexes, C-terminal epitope tagging of COX15 selectively affects its association to cytochrome c oxidase assembly intermediates (COA complexes). COX15 also forms complexes with maturing

COX1 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 ...

, the heme-receiving subunit of COX, in the absence of Shy1. ''COX15'' is positively regulated by intracellular heme levels via Huntingtin-associated protein 1.

References

External links

* {{UCSC gene info, COX15