DJ-1 — Mediated Wiki

{{Short description|Protein-coding gene found in humans}} {{Infobox_gene}} '''DJ1''', also known as '''Parkinson disease protein 7''', is a protein which in humans is encoded by the ''PARK7'' gene.<ref name="entrez">{{cite web | title = Entrez Gene: PARK7 | url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=11315}}</ref> Its weak glyoxalase activity has been verified by many labs,<ref>{{Cite journal |last1=Andreeva |first1=Anna |last2=Bekkhozhin |first2=Zhanibek |last3=Omertassova |first3=Nuriza |last4=Baizhumanov |first4=Timur |last5=Yeltay |first5=Gaziza |last6=Akhmetali |first6=Mels |last7=Toibazar |first7=Daulet |last8=Utepbergenov |first8=Darkhan |date=2019-12-06 |title=The apparent deglycase activity of DJ-1 results from the conversion of free methylglyoxal present in fast equilibrium with hemithioacetals and hemiaminals |journal=Journal of Biological Chemistry |language=en |volume=294 |issue=49 |pages=18863–18872 |doi=10.1074/jbc.RA119.011237 |doi-access=free |pmc=6901308 |pmid=31653696}}</ref><ref>{{Cite journal |last1=Choi |first1=Joonhyeok |last2=Tak |first2=Sungho |last3=Jung |first3=Hoe-Myung |last4=Cha |first4=Soyoung |last5=Hwang |first5=Eunha |last6=Lee |first6=Donghan |last7=Lee |first7=Joon-Hwa |last8=Ryu |first8=Kyoung-Seok |last9=Park |first9=Chankyu |date=May 2023 |title=Kinetic evidence in favor of glyoxalase III and against deglycase activity of DJ -1 |journal=Protein Science |language=en |volume=32 |issue=5 |doi=10.1002/pro.4641 |issn=0961-8368 |pmc=10127264 |pmid=37060572}}</ref> 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|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.<ref name="entrez"/>

=== 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.<ref>{{cite web|title=Uniprot: Q99497 - PARK7_HUMAN|url=https://www.uniprot.org/uniprot/Q99497}}</ref><ref>{{cite journal | vauthors = Honbou K, Suzuki NN, Horiuchi M, Niki T, Taira T, Ariga H, Inagaki F | title = The crystal structure of DJ-1, a protein related to male fertility and Parkinson's disease | journal = The Journal of Biological Chemistry | volume = 278 | issue = 33 | pages = 31380–4 | date = Aug 2003 | pmid = 12796482 | doi = 10.1074/jbc.M305878200 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Tao X, Tong L | title = Crystal structure of human DJ-1, a protein associated with early onset Parkinson's disease | journal = The Journal of Biological Chemistry | volume = 278 | issue = 33 | pages = 31372–9 | date = Aug 2003 | pmid = 12761214 | doi = 10.1074/jbc.M304221200 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Lee SJ, Kim SJ, Kim IK, Ko J, Jeong CS, Kim GH, Park C, Kang SO, Suh PG, Lee HS, Cha SS | title = Crystal structures of human DJ-1 and Escherichia coli Hsp31, which share an evolutionarily conserved domain | journal = The Journal of Biological Chemistry | volume = 278 | issue = 45 | pages = 44552–9 | date = Nov 2003 | pmid = 12939276 | doi = 10.1074/jbc.M304517200 | doi-access = free }}</ref>

== Function ==

DJ-1 was shown to prevent metabolite and protein damage caused by a glycolytic metabolite.<ref name=":0">{{Cite journal |last1=Heremans |first1=Isaac P. |last2=Caligiore |first2=Francesco |last3=Gerin |first3=Isabelle |last4=Bury |first4=Marina |last5=Lutz |first5=Marilena |last6=Graff |first6=Julie |last7=Stroobant |first7=Vincent |last8=Vertommen |first8=Didier |last9=Teleman |first9=Aurelio A. |last10=Van Schaftingen |first10=Emile |last11=Bommer |first11=Guido T. |date=2022-01-25 |title=Parkinson's disease protein PARK7 prevents metabolite and protein damage caused by a glycolytic metabolite |journal=Proceedings of the National Academy of Sciences |language=en |volume=119 |issue=4 |doi=10.1073/pnas.2111338119 |doi-access=free |issn=0027-8424 |pmc=8795555 |pmid=35046029|bibcode=2022PNAS..11911338H }}</ref> This metabolite has been suggested<ref name=":0" /> and confirmed<ref name=":1">{{Cite journal |last1=Akhmadi |first1=Aizhan |last2=Yeskendir |first2=Adilkhan |last3=Dey |first3=Nelly |last4=Mussakhmetov |first4=Arman |last5=Shatkenova |first5=Zariat |last6=Kulyyassov |first6=Arman |last7=Andreeva |first7=Anna |last8=Utepbergenov |first8=Darkhan |date=2024-03-05 |title=DJ-1 protects proteins from acylation by catalyzing the hydrolysis of highly reactive cyclic 3-phosphoglyceric anhydride |journal=Nature Communications |language=en |volume=15 |issue=1 |page=2004 |doi=10.1038/s41467-024-46391-9 |issn=2041-1723 |pmc=10915168 |pmid=38443379|bibcode=2024NatCo..15.2004A }}</ref> 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.<ref name=":1" />

Under an oxidative condition, DJ-1 inhibits the aggregation of α-synuclein via its chaperone activity,<ref>{{cite journal | vauthors = Shendelman S, Jonason A, Martinat C, Leete T, Abeliovich A | title = DJ-1 is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formation | journal = PLOS Biology | volume = 2 | issue = 11 | article-number = e362 | date = Nov 2004 | pmid = 15502874 | doi = 10.1371/journal.pbio.0020362 | pmc=521177 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Zhou W, Zhu M, Wilson MA, Petsko GA, Fink AL | title = The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein | journal = Journal of Molecular Biology | volume = 356 | issue = 4 | pages = 1036–48 | date = Mar 2006 | pmid = 16403519 | doi = 10.1016/j.jmb.2005.12.030 }}</ref> 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.<ref name="entrez" /> 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.<ref name="pmid31276729">{{cite journal | vauthors = Martín-Nieto J, Uribe ML, Esteve-Rudd J, Herrero MT, Campello L | title = A role for DJ-1 against oxidative stress in the mammalian retina | journal = Neurosci Lett | volume = 708 | issue = | article-number = 134361 | date = August 2019 | pmid = 31276729 | doi = 10.1016/j.neulet.2019.134361 | hdl=10045/94474|s2cid=195813073|hdl-access=free}}</ref><ref name="pmid23844142">{{cite journal | vauthors = Shadrach KG, Rayborn ME, Hollyfield JG, Bonilha VL | title = DJ-1-dependent regulation of oxidative stress in the retinal pigment epithelium (RPE) | journal = PLOS ONE | volume = 8 | issue = 7 | article-number = e67983 | date = 2013 | pmid = 23844142 | pmc = 3699467 | doi = 10.1371/journal.pone.0067983 | bibcode = 2013PLoSO...867983S|doi-access = free}}</ref>

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.<ref>{{cite journal | vauthors = Nunome K, Miyazaki S, Nakano M, Iguchi-Ariga S, Ariga H | title = Pyrroloquinoline quinone prevents oxidative stress-induced neuronal death probably through changes in oxidative status of DJ-1 | journal = Biological & Pharmaceutical Bulletin | volume = 31 | issue = 7 | pages = 1321–6 | date = Jul 2008 | pmid = 18591768 | doi = 10.1248/bpb.31.1321 | hdl = 2115/53726 | hdl-access = free }}</ref>

Functional DJ-1 protein has been shown to bind metals and protect against metal-induced cytotoxicity from copper and mercury.<ref name="pmid23792957">{{cite journal | vauthors = Björkblom B, Adilbayeva A, Maple-Grødem J, Piston D, Ökvist M, Xu XM, Brede C, Larsen JP, Møller SG | title = Parkinson disease protein DJ-1 binds metals and protects against metal-induced cytotoxicity. | journal = Journal of Biological Chemistry | year = 2013 | volume = 288 | issue = 31 | pages = 22809–20 | pmid = 23792957 | doi = 10.1074/jbc.M113.482091 | pmc = 3829365 | doi-access = free }} </ref>

DJ-1/''PARK7'' and its bacterial homologs: Hsp31, YhbO, and YajL can repair methylglyoxal and glyoxal glycated nucleotides.<ref name = Richarme2017>{{cite journal | vauthors = Richarme G, Liu C, Mihoub M, Abdallah J, Leger T, Joly N, Liebart JC, Jurkunas UV, Nadal M, Bouloc P, Dairou J, Lamouri A | title = Guanine glycation repair by DJ-1/Park7 and its bacterial homologs | journal = Science | volume = 357 | issue = 6347 | pages = 208–211 | date = July 2017 | pmid = 28596309 | doi = 10.1126/science.aag1095 | bibcode = 2017Sci...357..208R | doi-access = free }}</ref> 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''.<ref name = Richarme2017/> Deglycase-deficient bacterial mutants with reduced ability to repair glycated bases in DNA show strong mutator phenotypes.<ref name = Richarme2017/> 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.<ref>{{Cite journal |last1=Mazza |first1=Melissa Conti |last2=Shuck |first2=Sarah C. |last3=Lin |first3=Jiusheng |last4=Moxley |first4=Michael A. |last5=Termini |first5=John |last6=Cookson |first6=Mark R. |last7=Wilson |first7=Mark A. |date=August 2022 |title=DJ -1 is not a deglycase and makes a modest contribution to cellular defense against methylglyoxal damage in neurons |journal=Journal of Neurochemistry |language=en |volume=162 |issue=3 |pages=245–261 |doi=10.1111/jnc.15656 |issn=0022-3042 |pmc=9539984 |pmid=35713360}}</ref>

===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.<ref name = Wang2023>{{cite journal |vauthors=Wang ZX, Liu Y, Li YL, Wei Q, Lin RR, Kang R, Ruan Y, Lin ZH, Xue NJ, Zhang BR, Pu JL |title=Nuclear DJ-1 Regulates DNA Damage Repair via the Regulation of PARP1 Activity |journal=Int J Mol Sci |volume=24 |issue=10 |date=May 2023 |page=8651 |pmid=37239999 |pmc=10218208 |doi=10.3390/ijms24108651 |doi-access=free}}</ref> Evidence for a linkage between DNA damage and Parkinson's disease has been reported for decades.<ref name = Wang2023/> 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.<ref name = Wang2023/>

== Clinical significance ==

Defects in this gene are the cause of autosomal recessive early-onset Parkinson's disease 7.<ref name="entrez"/><ref name="pmid 12446870">{{cite journal | vauthors = 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 | title = Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism | journal = Science | volume = 299 | issue = 5604 | pages = 256–9 | date = Jan 2003 | pmid = 12446870 | doi = 10.1126/science.1077209 | bibcode = 2003Sci...299..256B | s2cid = 27186691 }}</ref>

== Interactions ==

''PARK7'' has been shown to interact with: * CASK,<ref name="pmid25071438">{{cite journal | vauthors = Mukherjee K, Slawson JB, Christmann BL, Griffith LC | title = Neuron-specific protein interactions of Drosophila CASK-β are revealed by mass spectrometry | journal = Frontiers in Molecular Neuroscience | volume = 7 | page = 58 | year = 2014 | pmid = 25071438 | pmc = 4075472 | doi = 10.3389/fnmol.2014.00058 | doi-access = free }}</ref> * EFCAB6,<ref name = pmid12612053>{{cite journal | vauthors = Niki T, Takahashi-Niki K, Taira T, Iguchi-Ariga SM, Ariga H | title = 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 | journal = Molecular Cancer Research | volume = 1 | issue = 4 | pages = 247–61 | date = Feb 2003 | pmid = 12612053 }}</ref> and * PIAS2.<ref name = pmid11477070>{{cite journal | vauthors = Takahashi K, Taira T, Niki T, Seino C, Iguchi-Ariga SM, Ariga H | title = DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx alpha to the receptor | journal = The Journal of Biological Chemistry | volume = 276 | issue = 40 | pages = 37556–63 | date = Oct 2001 | pmid = 11477070 | doi = 10.1074/jbc.M101730200 | doi-access = free }}</ref>

== References == {{Reflist|33em}}

== Further reading == {{refbegin|33em}} * {{cite journal | vauthors = Cookson MR | title = Pathways to Parkinsonism | journal = Neuron | volume = 37 | issue = 1 | pages = 7–10 | date = Jan 2003 | pmid = 12526767 | doi = 10.1016/S0896-6273(02)01166-2 | s2cid = 14513509 | doi-access = free }} * {{cite journal | vauthors = Bonifati V, Oostra BA, Heutink P | title = Linking DJ-1 to neurodegeneration offers novel insights for understanding the pathogenesis of Parkinson's disease | journal = Journal of Molecular Medicine | volume = 82 | issue = 3 | pages = 163–74 | date = Mar 2004 | pmid = 14712351 | doi = 10.1007/s00109-003-0512-1 | s2cid = 32685319 }} * {{cite journal | vauthors = Le W, Appel SH | title = Mutant genes responsible for Parkinson's disease | journal = Current Opinion in Pharmacology | volume = 4 | issue = 1 | pages = 79–84 | date = Feb 2004 | pmid = 15018843 | doi = 10.1016/j.coph.2003.09.005 }} * {{cite journal | vauthors = Abou-Sleiman PM, Healy DG, Wood NW | title = Causes of Parkinson's disease: genetics of DJ-1 | journal = Cell and Tissue Research | volume = 318 | issue = 1 | pages = 185–8 | date = Oct 2004 | pmid = 15503154 | doi = 10.1007/s00441-004-0922-6 | s2cid = 9453283 }} * {{cite journal | vauthors = Pankratz N, Foroud T | title = Genetics of Parkinson disease | journal = NeuroRx | volume = 1 | issue = 2 | pages = 235–42 | date = Apr 2004 | pmid = 15717024 | pmc = 534935 | doi = 10.1602/neurorx.1.2.235 }} * {{cite book | vauthors = Heutink P | chapter = PINK-1 and DJ-1 — new genes for autosomal recessive Parkinson's disease | title = Parkinson's Disease and Related Disorders | volume = 70 | issue = 70 | pages = 215–9 | year = 2006 | pmid = 17017532 | doi = 10.1007/978-3-211-45295-0_33 | isbn = 978-3-211-28927-3 | series = Journal of Neural Transmission. Supplementa }} * {{cite journal | vauthors = Lev N, Roncevic D, Roncevich D, Ickowicz D, Melamed E, Offen D | title = Role of DJ-1 in Parkinson's disease | journal = Journal of Molecular Neuroscience | volume = 29 | issue = 3 | pages = 215–25 | year = 2007 | pmid = 17085780 | doi = 10.1385/JMN:29:3:215 | s2cid = 85481215 }} * {{cite journal | vauthors = Nagakubo D, Taira T, Kitaura H, Ikeda M, Tamai K, Iguchi-Ariga SM, Ariga H | title = DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras | journal = Biochemical and Biophysical Research Communications | volume = 231 | issue = 2 | pages = 509–13 | date = Feb 1997 | pmid = 9070310 | doi = 10.1006/bbrc.1997.6132 }} * {{cite journal | vauthors = Taira T, Takahashi K, Kitagawa R, Iguchi-Ariga SM, Ariga H | title = Molecular cloning of human and mouse DJ-1 genes and identification of Sp1-dependent activation of the human DJ-1 promoter | journal = Gene | volume = 263 | issue = 1–2 | pages = 285–92 | date = Jan 2001 | pmid = 11223268 | doi = 10.1016/S0378-1119(00)00590-4 }} * {{cite journal | vauthors = van Duijn CM, Dekker MC, Bonifati V, Galjaard RJ, Houwing-Duistermaat JJ, Snijders PJ, Testers L, Breedveld GJ, Horstink M, Sandkuijl LA, van Swieten JC, Oostra BA, Heutink P | title = Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36 | journal = American Journal of Human Genetics | volume = 69 | issue = 3 | pages = 629–34 | date = Sep 2001 | pmid = 11462174 | pmc = 1235491 | doi = 10.1086/322996 }} * {{cite journal | vauthors = Takahashi K, Taira T, Niki T, Seino C, Iguchi-Ariga SM, Ariga H | title = DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx alpha to the receptor | journal = The Journal of Biological Chemistry | volume = 276 | issue = 40 | pages = 37556–63 | date = Oct 2001 | pmid = 11477070 | doi = 10.1074/jbc.M101730200 | doi-access = free }} * {{cite journal | vauthors = Bonifati V, Dekker MC, Vanacore N, Fabbrini G, Squitieri F, Marconi R, Antonini A, Brustenghi P, Dalla Libera A, De Mari M, Stocchi F, Montagna P, Gallai V, Rizzu P, van Swieten JC, Oostra B, van Duijn CM, Meco G, Heutink P | title = Autosomal recessive early onset parkinsonism is linked to three loci: PARK2, PARK6, and PARK7 | journal = Neurological Sciences | volume = 23 | pages = S59-60 | date = Sep 2002 | issue = Suppl 2 | pmid = 12548343 | doi = 10.1007/s100720200069 | s2cid = 13625056 }} * {{cite journal | vauthors = Dekker M, Bonifati V, van Swieten J, Leenders N, Galjaard RJ, Snijders P, Horstink M, Heutink P, Oostra B, van Duijn C | title = Clinical features and neuroimaging of PARK7-linked parkinsonism | journal = Movement Disorders | volume = 18 | issue = 7 | pages = 751–7 | date = Jul 2003 | pmid = 12815653 | doi = 10.1002/mds.10422 | s2cid = 44253517 }} * {{cite journal | vauthors = Miller DW, Ahmad R, Hague S, Baptista MJ, Canet-Aviles R, McLendon C, Carter DM, Zhu PP, Stadler J, Chandran J, Klinefelter GR, Blackstone C, Cookson MR | title = L166P mutant DJ-1, causative for recessive Parkinson's disease, is degraded through the ubiquitin-proteasome system | journal = The Journal of Biological Chemistry | volume = 278 | issue = 38 | pages = 36588–95 | date = Sep 2003 | pmid = 12851414 | doi = 10.1074/jbc.M304272200 | doi-access = free }} {{refend}}

== External links == * {{PDBe-KB2|Q99497|Protein/nucleic acid deglycase DJ-1}}