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DJ1, also known as Parkinson disease protein 7, is a protein which in humans is encoded by the PARK7 gene.[5] Its weak glyoxalase activity has been verified by many labs,[6][7] however the reported protein deglycase activity is likely to be an artifact stemming from DJ-1’s ability to destroy free methylglyoxal.

Structure

Gene

For C56, see MEROPS.

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.[5]

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.[8][9][10] 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.[11]

Function

DJ-1 was shown to prevent metabolite and protein damage caused by a glycolytic metabolite.[12] This metabolite has been suggested[12] and confirmed[13] 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.[13]

Under an oxidative condition, DJ-1 inhibits the aggregation of α-synuclein via its chaperone activity,[14][15] 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.[5] 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.[16][17]

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.[18]

Functional DJ-1 protein has been shown to bind metals and protect against metal-induced cytotoxicity from copper and mercury.[19]

DJ-1/PARK7 and its bacterial homologs: Hsp31, YhbO, and YajL can repair methylglyoxal and glyoxal glycated nucleotides.[20] 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.[20] Deglycase-deficient bacterial mutants with reduced ability to repair glycated bases in DNA show strong mutator phenotypes.[20] 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.[21]

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.[22] Evidence for a linkage between DNA damage and Parkinson’s disease has been reported for decades.[22] 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.[22]

Clinical significance

Defects in this gene are the cause of autosomal recessive early-onset Parkinson’s disease 7.[5][23]

Interactions

PARK7 has been shown to interact with:

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000116288 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028964 – Ensembl, May 2017
  3. ^ “Human PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ “Mouse PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c d “Entrez Gene: PARK7”.
  6. ^ Andreeva A, Bekkhozhin Z, Omertassova N, Baizhumanov T, Yeltay G, Akhmetali M, et al. (December 2019). “The apparent deglycase activity of DJ-1 results from the conversion of free methylglyoxal present in fast equilibrium with hemithioacetals and hemiaminals”. The Journal of Biological Chemistry. 294 (49): 18863–18872. doi:10.1074/jbc.RA119.011237. PMC 6901308. PMID 31653696.
  7. ^ Choi J, Tak S, Jung HM, Cha S, Hwang E, Lee D, et al. (May 2023). “Kinetic evidence in favor of glyoxalase III and against deglycase activity of DJ-1”. Protein Science. 32 (5) e4641. doi:10.1002/pro.4641. PMC 10127264. PMID 37060572.
  8. ^ “Uniprot: Q99497 – PARK7_HUMAN”. UniProt.
  9. ^ Honbou K, Suzuki NN, Horiuchi M, Niki T, Taira T, Ariga H, et al. (August 2003). “The crystal structure of DJ-1, a protein related to male fertility and Parkinson’s disease”. The Journal of Biological Chemistry. 278 (33): 31380–31384. doi:10.1074/jbc.M305878200. PMID 12796482.
  10. ^ Tao X, Tong L (August 2003). “Crystal structure of human DJ-1, a protein associated with early onset Parkinson’s disease”. The Journal of Biological Chemistry. 278 (33): 31372–31379. doi:10.1074/jbc.M304221200. PMID 12761214.
  11. ^ Lee SJ, Kim SJ, Kim IK, Ko J, Jeong CS, Kim GH, et al. (November 2003). “Crystal structures of human DJ-1 and Escherichia coli Hsp31, which share an evolutionarily conserved domain”. The Journal of Biological Chemistry. 278 (45): 44552–44559. doi:10.1074/jbc.M304517200. PMID 12939276.
  12. ^ a b Heremans IP, Caligiore F, Gerin I, Bury M, Lutz M, Graff J, et al. (January 2022). “Parkinson’s disease protein PARK7 prevents metabolite and protein damage caused by a glycolytic metabolite”. Proceedings of the National Academy of Sciences of the United States of America. 119 (4) e2111338119. Bibcode:2022PNAS..11911338H. doi:10.1073/pnas.2111338119. PMC 8795555. PMID 35046029.
  13. ^ a b Akhmadi A, Yeskendir A, Dey N, Mussakhmetov A, Shatkenova Z, Kulyyassov A, et al. (March 2024). “DJ-1 protects proteins from acylation by catalyzing the hydrolysis of highly reactive cyclic 3-phosphoglyceric anhydride”. Nature Communications. 15 (1) 2004. Bibcode:2024NatCo..15.2004A. doi:10.1038/s41467-024-46391-9. PMC 10915168. PMID 38443379.
  14. ^ Shendelman S, Jonason A, Martinat C, Leete T, Abeliovich A (November 2004). “DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation”. PLoS Biology. 2 (11) e362. doi:10.1371/journal.pbio.0020362. PMC 521177. PMID 15502874.
  15. ^ Zhou W, Zhu M, Wilson MA, Petsko GA, Fink AL (March 2006). “The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein”. Journal of Molecular Biology. 356 (4): 1036–1048. doi:10.1016/j.jmb.2005.12.030. PMID 16403519.
  16. ^ Martín-Nieto J, Uribe ML, Esteve-Rudd J, Herrero MT, Campello L (August 2019). “A role for DJ-1 against oxidative stress in the mammalian retina”. Neuroscience Letters. 708 134361. doi:10.1016/j.neulet.2019.134361. hdl:10045/94474. PMID 31276729. S2CID 195813073.
  17. ^ Shadrach KG, Rayborn ME, Hollyfield JG, Bonilha VL (2013). “DJ-1-dependent regulation of oxidative stress in the retinal pigment epithelium (RPE)”. PLOS ONE. 8 (7) e67983. Bibcode:2013PLoSO…867983S. doi:10.1371/journal.pone.0067983. PMC 3699467. PMID 23844142.
  18. ^ Nunome K, Miyazaki S, Nakano M, Iguchi-Ariga S, Ariga H (July 2008). “Pyrroloquinoline quinone prevents oxidative stress-induced neuronal death probably through changes in oxidative status of DJ-1”. Biological & Pharmaceutical Bulletin. 31 (7): 1321–1326. doi:10.1248/bpb.31.1321. hdl:2115/53726. PMID 18591768.
  19. ^ Björkblom B, Adilbayeva A, Maple-Grødem J, Piston D, Ökvist M, Xu XM, et al. (2013). “Parkinson disease protein DJ-1 binds metals and protects against metal-induced cytotoxicity”. The Journal of Biological Chemistry. 288 (31): 22809–22820. doi:10.1074/jbc.M113.482091. PMC 3829365. PMID 23792957.
  20. ^ a b c Richarme G, Liu C, Mihoub M, Abdallah J, Leger T, Joly N, et al. (July 2017). “Guanine glycation repair by DJ-1/Park7 and its bacterial homologs”. Science. 357 (6347). New York, N.Y.: 208–211. Bibcode:2017Sci…357..208R. doi:10.1126/science.aag1095. PMID 28596309.
  21. ^ Mazza MC, Shuck SC, Lin J, Moxley MA, Termini J, Cookson MR, et al. (August 2022). “DJ-1 is not a deglycase and makes a modest contribution to cellular defense against methylglyoxal damage in neurons”. Journal of Neurochemistry. 162 (3): 245–261. doi:10.1111/jnc.15656. PMC 9539984. PMID 35713360.
  22. ^ a b c Wang ZX, Liu Y, Li YL, Wei Q, Lin RR, Kang R, et al. (May 2023). “Nuclear DJ-1 Regulates DNA Damage Repair via the Regulation of PARP1 Activity”. International Journal of Molecular Sciences. 24 (10): 8651. doi:10.3390/ijms24108651. PMC 10218208. PMID 37239999.
  23. ^ Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, et al. (January 2003). “Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism”. Science. 299 (5604). New York, N.Y.: 256–259. Bibcode:2003Sci…299..256B. doi:10.1126/science.1077209. PMID 12446870. S2CID 27186691.
  24. ^ Mukherjee K, Slawson JB, Christmann BL, Griffith LC (2014). “Neuron-specific protein interactions of Drosophila CASK-β are revealed by mass spectrometry”. Frontiers in Molecular Neuroscience. 7 58. doi:10.3389/fnmol.2014.00058. PMC 4075472. PMID 25071438.
  25. ^ Niki T, Takahashi-Niki K, Taira T, Iguchi-Ariga SM, Ariga H (February 2003). “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): 247–261. PMID 12612053.
  26. ^ Takahashi K, Taira T, Niki T, Seino C, Iguchi-Ariga SM, Ariga H (October 2001). “DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx alpha to the receptor”. The Journal of Biological Chemistry. 276 (40): 37556–37563. doi:10.1074/jbc.M101730200. PMID 11477070.

Further reading

  • Overview of all the structural information available in the PDB for UniProt: Q99497 (Protein/nucleic acid deglycase DJ-1) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.