PARK7
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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 exons and locates at chromosome band 1p36.23.


Protein

The human protein DJ-1 is 20 kDa in size and composed of 189 amino acids with seven β-strands and nine α-helices in total and is present as a dimer. It belongs to the peptidase 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 via its chaperone activity, thus functioning as a redox-sensitive chaperone and as a sensor for oxidative stress. 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 of mammals, where it exerts a neuroprotective role against oxidative stress under both physiological and pathological conditions. Pyrroloquinoline quinone (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. Functional DJ-1 protein has been shown to bind metals and protect against metal-induced cytotoxicity from copper and mercury. DJ-1/''PARK7'' and its bacterial homologs: Hsp31, YhbO, and YajL can repair methylglyoxal and glyoxal 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 ...
s.
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 or
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 phenotypes. 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 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 and homologous recombination. Evidence for a linkage between DNA damage and Parkinson's disease 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 Parkinson's disease 7.


Interactions

''PARK7'' has been shown to interact with: * CASK, *
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.


See also

* Animal models of Parkinson's disease * Mitochondria associated membranes * Stress granule


References


Further reading

* * * * * * * * * * * * * *


External links

* {{NLM content