DJ-1 explained

Protein deglycase DJ-1, also known as Parkinson disease protein 7, is a protein which in humans is encoded by the PARK7 gene.[1]

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.[1]

Protein

The human protein deglycase 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.[2] [3] [4] It belongs to the peptidase C56 family of proteins.

The protein structures of human protein DJ-1, Escherichia coli chaperone Hsp31, YhbO, and YajL and an Archaea protease are evolutionarily conserved.[5]

Function

Under an oxidative condition, protein deglycase DJ-1 inhibits the aggregation of α-synuclein via its chaperone activity,[6] [7] 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.[1] In parallel, protein DJ-1 acts as a positive regulator of androgen receptor-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.[8] [9]

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.[10]

Functional DJ-1 protein has been shown to bind metals and protect against metal-induced cytotoxicity from copper and mercury.[11]

DJ-1/PARK7 and its bacterial homologs: Hsp31, YhbO, and YajL can repair methylglyoxal and glyoxal glycated nucleotides.[12] Guanine, either in the form of a free nucleotide or as a nucleotide incorporated into nucleic acid (DNA or RNA), if glycated, can be repaired by DJ-1/PARK7.[12] Deglycase-deficient bacterial mutants with reduced ability to repair glycated bases in DNA show strong mutator phenotypes.[12]

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.[13] Evidence for a linkage between DNA damage and Parkinson's disease has been reported for decades.[13] 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.[13]

Clinical significance

Defects in this gene are the cause of autosomal recessive early-onset Parkinson's disease 7.[1] [14]

Interactions

PARK7 has been shown to interact with:

See also

Further reading

Notes and References

  1. Web site: Entrez Gene: PARK7 .
  2. Web site: Uniprot: Q99497 - PARK7_HUMAN.
  3. Honbou K, Suzuki NN, Horiuchi M, Niki T, Taira T, Ariga H, Inagaki F . The crystal structure of DJ-1, a protein related to male fertility and Parkinson's disease . The Journal of Biological Chemistry . 278 . 33 . 31380–4 . Aug 2003 . 12796482 . 10.1074/jbc.M305878200 . free .
  4. Tao X, Tong L . Crystal structure of human DJ-1, a protein associated with early onset Parkinson's disease . The Journal of Biological Chemistry . 278 . 33 . 31372–9 . Aug 2003 . 12761214 . 10.1074/jbc.M304221200 . free .
  5. Lee SJ, Kim SJ, Kim IK, Ko J, Jeong CS, Kim GH, Park C, Kang SO, Suh PG, Lee HS, Cha SS . Crystal structures of human DJ-1 and Escherichia coli Hsp31, which share an evolutionarily conserved domain . The Journal of Biological Chemistry . 278 . 45 . 44552–9 . Nov 2003 . 12939276 . 10.1074/jbc.M304517200 . free .
  6. Shendelman S, Jonason A, Martinat C, Leete T, Abeliovich A . DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation . PLOS Biology . 2 . 11 . e362 . Nov 2004 . 15502874 . 10.1371/journal.pbio.0020362 . 521177 . free .
  7. Zhou W, Zhu M, Wilson MA, Petsko GA, Fink AL . The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein . Journal of Molecular Biology . 356 . 4 . 1036–48 . Mar 2006 . 16403519 . 10.1016/j.jmb.2005.12.030 .
  8. Martín-Nieto J, Uribe ML, Esteve-Rudd J, Herrero MT, Campello L . A role for DJ-1 against oxidative stress in the mammalian retina . Neurosci Lett . 708 . 134361 . August 2019 . 31276729 . 10.1016/j.neulet.2019.134361 . 10045/94474. 195813073. free.
  9. Shadrach KG, Rayborn ME, Hollyfield JG, Bonilha VL . DJ-1-dependent regulation of oxidative stress in the retinal pigment epithelium (RPE) . PLOS ONE . 8 . 7 . e67983 . 2013 . 23844142 . 3699467 . 10.1371/journal.pone.0067983 . 2013PLoSO...867983S. free.
  10. Nunome K, Miyazaki S, Nakano M, Iguchi-Ariga S, Ariga H . Pyrroloquinoline quinone prevents oxidative stress-induced neuronal death probably through changes in oxidative status of DJ-1 . Biological & Pharmaceutical Bulletin . 31 . 7 . 1321–6 . Jul 2008 . 18591768 . 10.1248/bpb.31.1321 . 2115/53726 . free .
  11. Björkblom B, Adilbayeva A, Maple-Grødem J, Piston D, Ökvist M, Xu XM, Brede C, Larsen JP, Møller SG . Parkinson disease protein DJ-1 binds metals and protects against metal-induced cytotoxicity. . Journal of Biological Chemistry . 2013 . 288 . 31 . 22809–20 . 23792957 . 10.1074/jbc.M113.482091 . 3829365 . free .
  12. Richarme G, Liu C, Mihoub M, Abdallah J, Leger T, Joly N, Liebart JC, Jurkunas UV, Nadal M, Bouloc P, Dairou J, Lamouri A . Guanine glycation repair by DJ-1/Park7 and its bacterial homologs . Science . 357 . 6347 . 208–211 . July 2017 . 28596309 . 10.1126/science.aag1095 . 2017Sci...357..208R . free .
  13. Wang ZX, Liu Y, Li YL, Wei Q, Lin RR, Kang R, Ruan Y, Lin ZH, Xue NJ, Zhang BR, Pu JL . Nuclear DJ-1 Regulates DNA Damage Repair via the Regulation of PARP1 Activity . Int J Mol Sci . 24 . 10 . May 2023 . 37239999 . 10218208 . 10.3390/ijms24108651 . free.
  14. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P . Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism . Science . 299 . 5604 . 256–9 . Jan 2003 . 12446870 . 10.1126/science.1077209 . 2003Sci...299..256B . 27186691 .
  15. Mukherjee K, Slawson JB, Christmann BL, Griffith LC . Neuron-specific protein interactions of Drosophila CASK-β are revealed by mass spectrometry . Frontiers in Molecular Neuroscience . 7 . 58 . 2014 . 25071438 . 4075472 . 10.3389/fnmol.2014.00058 . free .
  16. Niki T, Takahashi-Niki K, Taira T, Iguchi-Ariga SM, Ariga H . DJBP: a novel DJ-1-binding protein, negatively regulates the androgen receptor by recruiting histone deacetylase complex, and DJ-1 antagonizes this inhibition by abrogation of this complex . Molecular Cancer Research . 1 . 4 . 247–61 . Feb 2003 . 12612053 .
  17. Takahashi K, Taira T, Niki T, Seino C, Iguchi-Ariga SM, Ariga H . DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx alpha to the receptor . The Journal of Biological Chemistry . 276 . 40 . 37556–63 . Oct 2001 . 11477070 . 10.1074/jbc.M101730200 . free .