| Structural highlights
Disease
[PARK7_HUMAN] Defects in PARK7 are the cause of Parkinson disease type 7 (PARK7) [MIM:606324]. A neurodegenerative disorder characterized by resting tremor, postural tremor, bradykinesia, muscular rigidity, anxiety and psychotic episodes. PARK7 has onset before 40 years, slow progression and initial good response to levodopa. Some patients may show traits reminiscent of amyotrophic lateral sclerosis-parkinsonism/dementia complex (Guam disease).[1] [2] [3] [4] [5] [6] [7] [8]
Function
[PARK7_HUMAN] Protects cells against oxidative stress and cell death. Plays a role in regulating expression or stability of the mitochondrial uncoupling proteins SLC25A14 and SLC25A27 in dopaminergic neurons of the substantia nigra pars compacta and attenuates the oxidative stress induced by calcium entry into the neurons via L-type channels during pacemaking. Eliminates hydrogen peroxide and protects cells against hydrogen peroxide-induced cell death. May act as an atypical peroxiredoxin-like peroxidase that scavenges hydrogen peroxide. Following removal of a C-terminal peptide, displays protease activity and enhanced cytoprotective action against oxidative stress-induced apoptosis. Stabilizes NFE2L2 by preventing its association with KEAP1 and its subsequent ubiquitination. Binds to OTUD7B and inhibits its deubiquitinating activity. Enhances RELA nuclear translocation. Binds to a number of mRNAs containing multiple copies of GG or CC motifs and partially inhibits their translation but dissociates following oxidative stress. Required for correct mitochondrial morphology and function and for autophagy of dysfunctional mitochondria. Regulates astrocyte inflammatory responses. Acts as a positive regulator of androgen receptor-dependent transcription. Prevents aggregation of SNCA. Plays a role in fertilization. Has no proteolytic activity. Has cell-growth promoting activity and transforming activity. May function as a redox-sensitive chaperone.[9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22]
Publication Abstract from PubMed
Mutations in the human protein DJ-1 cause early onset of Parkinson's disease. A reactive cysteine residue (Cys(106)) of DJ-1 is crucial for its protective function, although the underlying mechanisms are unclear. Here we show that a fraction of bacterially expressed polyhistidine-tagged human DJ-1 could not be eluted from a Ni-nitrilotriacetate (Ni-NTA) column with 150mM imidazole. This unusually tight binding was accompanied by the appearance of blue violet color on the Ni-NTA column. We demonstrate by X-ray crystallography that Cys(106) is carboxymethylated in a fraction of DJ-1 tightly bound to Ni-NTA and that the replacement of Cys(106) by serine abrogates the tight binding and the appearance of blue violet color. However, carboxymethylation of purified DJ-1 is insufficient to confer the tight binding to Ni-NTA. Moreover, when eluted protein was re-applied to the Ni-NTA column, no tight binding was observed, indicating that the formation of high affinity complex with Ni-NTA depends on a transient modification of Cys(106) that transforms into a Cys(106)-carboxymethyl adduct upon elution from Ni-NTA. We conclude that an unknown metabolite reacts with Cys(106) of DJ-1 to result in a transient post-translational modification. This modification is distinct from simple oxidation to sulfinic or sulfenic acids and confers altered binding properties to DJ-1 suggesting that it could serve as a signal for sensing oxidant stress.
A transient post-translational modification of active site cysteine alters binding properties of the parkinsonism protein DJ-1.,Mussakhmetov A, Shumilin IA, Nugmanova R, Shabalin IG, Baizhumanov T, Toibazar D, Khassenov B, Minor W, Utepbergenov D Biochem Biophys Res Commun. 2018 Sep 26;504(1):328-333. doi:, 10.1016/j.bbrc.2018.08.190. Epub 2018 Sep 4. PMID:30190129[23]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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. L166P mutant DJ-1, causative for recessive Parkinson's disease, is degraded through the ubiquitin-proteasome system. J Biol Chem. 2003 Sep 19;278(38):36588-95. Epub 2003 Jul 8. PMID:12851414 doi:10.1074/jbc.M304272200
- ↑ 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. 2003 Jan 10;299(5604):256-9. Epub 2002 Nov 21. PMID:12446870 doi:10.1126/science.1077209
- ↑ Moore DJ, Zhang L, Dawson TM, Dawson VL. A missense mutation (L166P) in DJ-1, linked to familial Parkinson's disease, confers reduced protein stability and impairs homo-oligomerization. J Neurochem. 2003 Dec;87(6):1558-67. PMID:14713311
- ↑ Abou-Sleiman PM, Healy DG, Quinn N, Lees AJ, Wood NW. The role of pathogenic DJ-1 mutations in Parkinson's disease. Ann Neurol. 2003 Sep;54(3):283-6. PMID:12953260 doi:http://dx.doi.org/10.1002/ana.10675
- ↑ Hering R, Strauss KM, Tao X, Bauer A, Woitalla D, Mietz EM, Petrovic S, Bauer P, Schaible W, Muller T, Schols L, Klein C, Berg D, Meyer PT, Schulz JB, Wollnik B, Tong L, Kruger R, Riess O. Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7). Hum Mutat. 2004 Oct;24(4):321-9. PMID:15365989 doi:10.1002/humu.20089
- ↑ Gorner K, Holtorf E, Odoy S, Nuscher B, Yamamoto A, Regula JT, Beyer K, Haass C, Kahle PJ. Differential effects of Parkinson's disease-associated mutations on stability and folding of DJ-1. J Biol Chem. 2004 Feb 20;279(8):6943-51. Epub 2003 Nov 7. PMID:14607841 doi:10.1074/jbc.M309204200
- ↑ Clark LN, Afridi S, Mejia-Santana H, Harris J, Louis ED, Cote LJ, Andrews H, Singleton A, Wavrant De-Vrieze F, Hardy J, Mayeux R, Fahn S, Waters C, Ford B, Frucht S, Ottman R, Marder K. Analysis of an early-onset Parkinson's disease cohort for DJ-1 mutations. Mov Disord. 2004 Jul;19(7):796-800. PMID:15254937 doi:10.1002/mds.20131
- ↑ Olzmann JA, Li L, Chudaev MV, Chen J, Perez FA, Palmiter RD, Chin LS. Parkin-mediated K63-linked polyubiquitination targets misfolded DJ-1 to aggresomes via binding to HDAC6. J Cell Biol. 2007 Sep 10;178(6):1025-38. PMID:17846173 doi:10.1083/jcb.200611128
- ↑ Nagakubo D, Taira T, Kitaura H, Ikeda M, Tamai K, Iguchi-Ariga SM, Ariga H. DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem Biophys Res Commun. 1997 Feb 13;231(2):509-13. PMID:9070310 doi:S0006-291X(97)96132-5
- ↑ 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. J Biol Chem. 2001 Oct 5;276(40):37556-63. Epub 2001 Jul 26. PMID:11477070 doi:10.1074/jbc.M101730200
- ↑ 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. Mol Cancer Res. 2003 Feb;1(4):247-61. PMID:12612053
- ↑ Taira T, Saito Y, Niki T, Iguchi-Ariga SM, Takahashi K, Ariga H. DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep. 2004 Feb;5(2):213-8. Epub 2004 Jan 23. PMID:14749723 doi:10.1038/sj.embor.7400074
- ↑ 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 Biol. 2004 Nov;2(11):e362. Epub 2004 Oct 5. PMID:15502874 doi:10.1371/journal.pbio.0020362
- ↑ Shinbo Y, Niki T, Taira T, Ooe H, Takahashi-Niki K, Maita C, Seino C, Iguchi-Ariga SM, Ariga H. Proper SUMO-1 conjugation is essential to DJ-1 to exert its full activities. Cell Death Differ. 2006 Jan;13(1):96-108. PMID:15976810 doi:4401704
- ↑ Sekito A, Koide-Yoshida S, Niki T, Taira T, Iguchi-Ariga SM, Ariga H. DJ-1 interacts with HIPK1 and affects H2O2-induced cell death. Free Radic Res. 2006 Feb;40(2):155-65. PMID:16390825 doi:10.1080/10715760500456847
- ↑ Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP. DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15091-6. Epub 2006 Oct 2. PMID:17015834 doi:10.1073/pnas.0607260103
- ↑ van der Brug MP, Blackinton J, Chandran J, Hao LY, Lal A, Mazan-Mamczarz K, Martindale J, Xie C, Ahmad R, Thomas KJ, Beilina A, Gibbs JR, Ding J, Myers AJ, Zhan M, Cai H, Bonini NM, Gorospe M, Cookson MR. RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways. Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10244-9. doi:, 10.1073/pnas.0708518105. Epub 2008 Jul 14. PMID:18626009 doi:10.1073/pnas.0708518105
- ↑ Junn E, Jang WH, Zhao X, Jeong BS, Mouradian MM. Mitochondrial localization of DJ-1 leads to enhanced neuroprotection. J Neurosci Res. 2009 Jan;87(1):123-9. doi: 10.1002/jnr.21831. PMID:18711745 doi:10.1002/jnr.21831
- ↑ Chen J, Li L, Chin LS. Parkinson disease protein DJ-1 converts from a zymogen to a protease by carboxyl-terminal cleavage. Hum Mol Genet. 2010 Jun 15;19(12):2395-408. doi: 10.1093/hmg/ddq113. Epub 2010, Mar 18. PMID:20304780 doi:10.1093/hmg/ddq113
- ↑ McNally RS, Davis BK, Clements CM, Accavitti-Loper MA, Mak TW, Ting JP. DJ-1 enhances cell survival through the binding of Cezanne, a negative regulator of NF-kappaB. J Biol Chem. 2011 Feb 11;286(6):4098-106. doi: 10.1074/jbc.M110.147371. Epub 2010, Nov 19. PMID:21097510 doi:10.1074/jbc.M110.147371
- ↑ 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. J Biol Chem. 2003 Nov 7;278(45):44552-9. Epub 2003 Aug 25. PMID:12939276 doi:http://dx.doi.org/10.1074/jbc.M304517200
- ↑ Canet-Aviles RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S, Baptista MJ, Ringe D, Petsko GA, Cookson MR. The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9103-8. Epub 2004 Jun 4. PMID:15181200 doi:10.1073/pnas.0402959101
- ↑ Mussakhmetov A, Shumilin IA, Nugmanova R, Shabalin IG, Baizhumanov T, Toibazar D, Khassenov B, Minor W, Utepbergenov D. A transient post-translational modification of active site cysteine alters binding properties of the parkinsonism protein DJ-1. Biochem Biophys Res Commun. 2018 Sep 26;504(1):328-333. doi:, 10.1016/j.bbrc.2018.08.190. Epub 2018 Sep 4. PMID:30190129 doi:http://dx.doi.org/10.1016/j.bbrc.2018.08.190
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