DJ1, also known as Parkinson disease protein 7, 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 ...

which in humans is encoded by the ''PARK7''

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 ...

. Its weak glyoxalase activity has been verified by many labs, however the reported protein deglycase activity is likely to be an artifact stemming from DJ-1's ability to destroy free methylglyoxal.

Structure

Gene

The gene ''PARK7'', also known as ''DJ-1'', encodes a protein of the peptidase C56 family. The human gene ''PARK7'' has 8

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 and locates at chromosome band 1p36.23.

Protein

The human protein DJ-1 is 20

kDa The dalton or unified atomic mass unit (symbols: Da or u, respectively) is a unit of mass defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at rest. It is a non-SI unit accepted f ...

in size and composed of 189 amino acids with seven

β-strand The beta sheet (β-sheet, also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gene ...

s and nine

α-helices An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...

in total and is present as a

dimer Dimer may refer to: * Dimer (chemistry), a chemical structure formed from two similar sub-units ** Protein dimer, a protein quaternary structure ** d-dimer ** TH-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * ...

. It belongs to the

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

C56 family of proteins. The protein structures of human protein DJ-1, ''

Escherichia coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Escherichia'' that is commonly fo ...

'' chaperone Hsp31, YhbO, and YajL and an

Archaea Archaea ( ) is a Domain (biology), domain of organisms. Traditionally, Archaea only included its Prokaryote, prokaryotic members, but this has since been found to be paraphyletic, as eukaryotes are known to have evolved from archaea. Even thou ...

protease are evolutionarily conserved.

Function

DJ-1 was shown to prevent metabolite and protein damage caused by a glycolytic metabolite. This metabolite has been suggested and confirmed to be cyclic 3-phosphoglycerate (or cyclic 3-phosphoglyceric anhydride). Catalytic efficiency of DJ-1 as a hydrolase of cyclic 3-phosphoglyceric anhydride is 10,000 times higher than other reported enzymatic activities of DJ-1. Under an oxidative condition, DJ-1 inhibits the aggregation of

α-synuclein Alpha-synuclein (aSyn) is a protein that in humans is encoded by the ''SNCA'' gene. It is a neuronal protein involved in the regulation of synaptic vesicle trafficking and the release of neurotransmitters. Alpha-synuclein is abundant in the bra ...

via its chaperone activity, thus functioning as a redox-sensitive chaperone and as a sensor for

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

. Accordingly, DJ-1 apparently protects neurons against oxidative stress and cell death. In parallel, protein DJ-1 acts as a positive regulator of

androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in th ...

-dependent transcription. DJ-1 is expressed in both the neural retina and

retinal pigment epithelium The pigmented layer of retina or retinal pigment epithelium (RPE) is the pigment A pigment is a powder used to add or alter color or change visual appearance. Pigments are completely or nearly solubility, insoluble and reactivity (chemistry), ...

of mammals, where it exerts a neuroprotective role against oxidative stress under both physiological and pathological conditions.

Pyrroloquinoline quinone Pyrroloquinoline quinone (PQQ), also called methoxatin'','' is a redox cofactor and antioxidant. Quinoprotein glucose dehydrogenase is used as a glucose sensor in bacteria. PQQ stimulates growth in bacteria. History It was discovered by J. G. ...

(PQQ) has been shown to reduce the self-oxidation of the DJ-1 protein, an early step in the onset of some forms of

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

. Functional DJ-1 protein has been shown to bind metals and protect against metal-induced cytotoxicity from

copper Copper is a chemical element; it has symbol Cu (from Latin ) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkish-orang ...

and mercury. DJ-1/''PARK7'' and its bacterial homologs: Hsp31, YhbO, and YajL can repair

methylglyoxal Methylglyoxal (MGO) is the organic compound with the formula CH3C(O)CHO. It is a reduced derivative of pyruvic acid. It is a reactive compound that is implicated in the biology of diabetes. Methylglyoxal is produced industrially by degradation ...

and

glyoxal Glyoxal is an organic compound with the chemical formula OCHCHO. It is the smallest dialdehyde (a compound with two aldehyde groups). It is a crystalline solid, white at low temperatures and yellow near the melting point (15 °C). The liquid ...

glycated

nucleotide Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...

Guanine Guanine () (symbol G or Gua) is one of the four main nucleotide bases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine ( uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside ...

, either in the form of a free nucleotide or as a nucleotide incorporated into

nucleic acid Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a pentose, 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nuclei ...

(

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...

), if glycated, can be repaired by DJ-1/''PARK7''. Deglycase-deficient bacterial mutants with reduced ability to repair glycated bases in DNA show strong

mutator 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 properties ...

s. A follow up study confirmed that DJ-1 reduces levels of reversible adducts of methylglyoxal with guanine and cysteine in vitro. However, since the steady-state kinetics of DJ-1 acting on reversible hemithioacetal substrates are fitted adequately with a computational kinetic model that requires only a DJ-1 glyoxalase activity, it was concluded that deglycation is an apparent rather than a true activity of DJ-1.

DNA repair

DJ-1 is a

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is constantly modified ...

response protein that is recruited to sites of DNA damage where it participates in the repair of DNA double-strand breaks through the processes of

non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair ...

and

homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in Cell (biology), cellular organi ...

. Evidence for a linkage between DNA damage and

has been reported for decades. Recently evidence has been presented that defective DNA repair is linked specifically to DJ-1 mutation, and thus DJ-1 mutation likely contributes to Parkinson's disease pathogenesis.

Clinical significance

Defects in this gene are the cause of autosomal recessive early-onset

Interactions

''PARK7'' has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...

with: *

CASK A barrel or cask is a hollow cylindrical container with a bulging center, longer than it is wide. They are traditionally made of wooden staves and bound by wooden or metal hoops. The word vat is often used for large containers for liquids ...

, *

EFCAB6 EF-hand calcium-binding domain-containing protein 6 is a protein that in humans is encoded by the ''EFCAB6'' gene. Interactions EFCAB6 has been shown to interact with PARK7 and Androgen receptor The androgen receptor (AR), also known as ...

, and *

PIAS2 E3 SUMO-protein ligase PIAS2 is an enzyme that in humans is encoded by the ''PIAS2'' gene. Interactions Protein inhibitor of activated STAT2 has been shown to interact with: * Androgen receptor, * DNMT3A, * PARK7, and * UBE2I SUMO-conjug ...

References

External links

* {{NLM content