{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:37:40Z","timestamp":1787067460299,"version":"build-2736575974"},"reference-count":42,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T00:00:00Z","timestamp":1728950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology Council, Taiwan","award":["NSTC 112-2113-M-029-002"],"award-info":[{"award-number":["NSTC 112-2113-M-029-002"]}]},{"name":"Ministry of Science and Technology Council, Taiwan","award":["NSTC 113-2923-M-029-002-MY3"],"award-info":[{"award-number":["NSTC 113-2923-M-029-002-MY3"]}]},{"name":"Ministry of Science and Technology Council, Taiwan","award":["NSTC 113-2113-M-029-011"],"award-info":[{"award-number":["NSTC 113-2113-M-029-011"]}]},{"name":"Ministry of Science and Technology Council, Taiwan","award":["NSTC 113-2113-M-029-003"],"award-info":[{"award-number":["NSTC 113-2113-M-029-003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>DJ-1 is a vital enzyme involved in the maintenance of mitochondrial health, and its mutation has been associated with an increased risk of Parkinson\u2019s disease (PD). Effective regulation of DJ-1 activity is essential for the well-being of mitochondria, and DJ-1 is thus a potential target for PD drug development. In this study, two peptides (15EEMETIIPVDVMRRA29 and 47SRDVVICPDA56) were utilized with the aim of enhancing the activity of DJ-1. The mechanisms underlying the activity enhancement by these two peptides were investigated using hydrogen\/deuterium exchange mass spectrometry (HDXMS). The HDXMS results revealed distinct mechanisms. Peptide 1 obstructs the access of solvent to the dimer interface and stabilizes the \u03b1\/\u03b2 hydrolase structure, facilitating substrate binding to a stabilized active site. Conversely, peptide 2 induces a destabilization of the \u03b1\/\u03b2 hydrolase core, enhancing substrate accessibility and subsequently increasing DJ-1 activity. The binding of these two peptides optimizes the activity site within the dimeric structure. These findings offer valuable insights into the mechanisms underlying the activity enhancement of DJ-1 by the two peptides, potentially aiding the development of new drugs that can enhance the activity of DJ-1 and, consequently, advance PD treatment.<\/jats:p>","DOI":"10.3390\/ijms252011075","type":"journal-article","created":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T08:09:08Z","timestamp":1728979748000},"page":"11075","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Peptide Activator Stabilizes DJ-1 Structure and Enhances Its Activity"],"prefix":"10.3390","volume":"25","author":[{"given":"Jing-Yuan","family":"Shih","sequence":"first","affiliation":[{"name":"Department of Chemistry, Tunghai University, No. 1727, Sec. 4, Taiwan Boulevard, Xitun District, Taichung 40704, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3423-2892","authenticated-orcid":false,"given":"Yuan-Hao Howard","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Tunghai University, No. 1727, Sec. 4, Taiwan Boulevard, Xitun District, Taichung 40704, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/0165-1781(79)90006-4","article-title":"Chronic Parkinsonism secondary to intravenous injection of meperidine analogues","volume":"1","author":"Davis","year":"1979","journal-title":"Psychiatry Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3038","DOI":"10.1038\/emboj.2012.170","article-title":"Mitochondrial dysfunction in Parkinson\u2019s disease: Molecular mechanisms and pathophysiological consequences","volume":"31","author":"Exner","year":"2012","journal-title":"EMBO J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.bbadis.2009.08.013","article-title":"Mitochondrial dysfunction in Parkinson\u2019s disease","volume":"1802","author":"Winklhofer","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/978-1-59745-521-3_11","article-title":"Reactive oxygen species production by mitochondria","volume":"554","author":"Lambert","year":"2009","journal-title":"Methods Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1126\/science.276.5321.2045","article-title":"Mutation in the alpha-synuclein gene identified in families with Parkinson\u2019s disease","volume":"276","author":"Polymeropoulos","year":"1997","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1056\/NEJM200005253422103","article-title":"Association between early-onset Parkinson\u2019s disease and mutations in the parkin gene","volume":"342","author":"Lucking","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1126\/science.1096284","article-title":"Hereditary early-onset Parkinson\u2019s disease caused by mutations in PINK1","volume":"304","author":"Valente","year":"2004","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1126\/science.1077209","article-title":"Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism","volume":"299","author":"Bonifati","year":"2003","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"406","DOI":"10.2353\/ajpath.2008.070823","article-title":"Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations","volume":"172","author":"Malik","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/S0378-1119(00)00590-4","article-title":"Molecular cloning of human and mouse DJ-1 genes and identification of Sp1-dependent activation of the human DJ-1 promoter","volume":"263","author":"Taira","year":"2001","journal-title":"Gene"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"a009415","DOI":"10.1101\/cshperspect.a009415","article-title":"Parkinsonism Due to Mutations in PINK1, Parkin, and DJ-1 and Oxidative Stress and Mitochondrial Pathways","volume":"2","author":"Cookson","year":"2012","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1038\/ncb1644","article-title":"The mitochondrial protease HtrA2 is regulated by Parkinson\u2019s disease-associated kinase PINK1","volume":"9","author":"Klupsch","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1371\/journal.pbio.0050172","article-title":"PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1","volume":"5","author":"Pridgeon","year":"2007","journal-title":"PLoS Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Narendra, D.P., Jin, S.M., Tanaka, A., Suen, D.F., Gautier, C.A., Shen, J., Cookson, M.R., and Youle, R.J. (2010). PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin. PLoS Biol., 8.","DOI":"10.1371\/journal.pbio.1000298"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1016\/j.bbagen.2017.03.013","article-title":"DJ-1, a Parkinson\u2019s disease related protein, aggregates under denaturing conditions and co-aggregates with alpha-synuclein through hydrophobic interaction","volume":"1861","author":"Zhu","year":"2017","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20940","DOI":"10.1074\/jbc.M601935200","article-title":"DJ-1 transcriptionally up-regulates the human tyrosine hydroxylase by inhibiting the sumoylation of pyrimidine tract-binding protein-associated splicing factor","volume":"281","author":"Zhong","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1093\/hmg\/ddx425","article-title":"DJ-1 is a redox sensitive adapter protein for high molecular weight complexes involved in regulation of catecholamine homeostasis","volume":"27","author":"Piston","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.nbd.2013.11.004","article-title":"Modulation of human alpha-synuclein aggregation by a combined effect of calcium and dopamine","volume":"63","author":"Jain","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1111\/j.1742-4658.2011.08093.x","article-title":"Modulation of alpha-synuclein aggregation by dopamine in the presence of MPTP and its metabolite","volume":"278","author":"Jethva","year":"2011","journal-title":"FEBS J."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Latawiec, D., Herrera, F., Bek, A., Losasso, V., Candotti, M., Benetti, F., Carlino, E., Kranjc, A., Lazzarino, M., and Gustincich, S. (2010). Modulation of alpha-synuclein aggregation by dopamine analogs. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009234"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1007\/s11064-009-9986-8","article-title":"Modulation of alpha-synuclein aggregation by dopamine: A review","volume":"34","author":"Leong","year":"2009","journal-title":"Neurochem. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.jmb.2009.02.007","article-title":"Dopamine and the dopamine oxidation product 5,6-dihydroxylindole promote distinct on-pathway and off-pathway aggregation of alpha-synuclein in a pH-dependent manner","volume":"387","author":"Pham","year":"2009","journal-title":"J. Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1093\/gerona\/gls147","article-title":"DJ-1 Protects Against Dopamine Toxicity: Implications for Parkinson\u2019s Disease and Aging","volume":"68","author":"Lev","year":"2013","journal-title":"J. Gerontol. A-Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s00702-008-0134-4","article-title":"DJ-1 protects against dopamine toxicity","volume":"116","author":"Lev","year":"2009","journal-title":"J. Neural Transm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/sj.embor.7400074","article-title":"DJ-1 has a role in antioxidative stress to prevent cell death","volume":"5","author":"Taira","year":"2004","journal-title":"Embo Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/cr.2015.63","article-title":"Park7 interacts with p47(phox) to direct NADPH oxidase-dependent ROS production and protect against sepsis","volume":"25","author":"Liu","year":"2015","journal-title":"Cell Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"43150","DOI":"10.1074\/jbc.M507124200","article-title":"DJ-1 up-regulates glutathione synthesis during oxidative stress and inhibits A53T alpha-synuclein toxicity","volume":"280","author":"Zhou","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.nbd.2018.04.008","article-title":"Astrocyte-specific DJ-1 overexpression protects against rotenone-induced neurotoxicity in a rat model of Parkinson\u2019s disease","volume":"115","author":"Rocha","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.jphs.2015.01.010","article-title":"DJ-1-dependent protective activity of DJ-1-binding compound no. 23 against neuronal cell death in MPTP-treated mouse model of Parkinson\u2019s disease","volume":"127","author":"Inafune","year":"2015","journal-title":"J. Pharmacol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"146641","DOI":"10.1016\/j.brainres.2019.146641","article-title":"DJ-1-binding compound B enhances Nrf2 activity through the PI3-kinase-Akt pathway by DJ-1-dependent inactivation of PTEN","volume":"1729","author":"Niki","year":"2020","journal-title":"Brain Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"De Miguel, C., Kraus, A.C., Saludes, M.A., Konkalmatt, P., Ruiz Dom\u00ednguez, A., Asico, L.D., Latham, P.S., Offen, D., Jose, P.A., and Cuevas, S. (2020). ND-13, a DJ-1-Derived Peptide, Attenuates the Renal Expression of Fibrotic and Inflammatory Markers Associated with Unilateral Ureter Obstruction. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197048"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1002\/jnr.21831","article-title":"Mitochondrial localization of DJ-1 leads to enhanced neuroprotection","volume":"87","author":"Junn","year":"2009","journal-title":"J. Neurosci. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4805","DOI":"10.1093\/hmg\/ddt332","article-title":"DJ-1 associates with lipid rafts by palmitoylation and regulates lipid rafts-dependent endocytosis in astrocytes","volume":"22","author":"Kim","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1074\/jbc.M114.597815","article-title":"Parkinsonism-associated Protein DJ-1\/Park7 Is a Major Protein Deglycase That Repairs Methylglyoxal- and Glyoxal-glycated Cysteine, Arginine, and Lysine Residues","volume":"290","author":"Richarme","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.jmb.2005.12.030","article-title":"The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein","volume":"356","author":"Zhou","year":"2006","journal-title":"J. Mol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"44552","DOI":"10.1074\/jbc.M304517200","article-title":"Crystal structures of human DJ-1 and Escherichia coli Hsp31, which share an evolutionarily conserved domain","volume":"278","author":"Lee","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1371\/journal.pcbi.0030010","article-title":"Identification of functional subclasses in the DJ-1 superfamily proteins","volume":"3","author":"Wei","year":"2007","journal-title":"PLoS Comput. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6476","DOI":"10.1074\/jbc.M806599200","article-title":"Formation of a Stabilized Cysteine Sulfinic Acid Is Critical for the Mitochondrial Function of the Parkinsonism Protein DJ-1","volume":"284","author":"Blackinton","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"31372","DOI":"10.1074\/jbc.M304221200","article-title":"Crystal structure of human DJ-1, a protein associated with early onset Parkinson\u2019s disease","volume":"278","author":"Tao","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"31380","DOI":"10.1074\/jbc.M305878200","article-title":"The crystal structure of DJ-1, a protein related to male fertility and Parkinson\u2019s disease","volume":"278","author":"Honbou","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S0014-5793(03)00764-6","article-title":"Crystal structure of DJ-1\/RS and implication on familial Parkinson\u2019s disease","volume":"549","author":"Huai","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"S127","DOI":"10.1016\/j.yjmcc.2022.08.249","article-title":"Novel nanoparticle improves intracellular uptake and cardioprotective efficacy of DJ-1 mimic peptide","volume":"173","author":"Lu","year":"2022","journal-title":"J. Mol. Cell Cardiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/20\/11075\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:13:44Z","timestamp":1760112824000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/20\/11075"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,15]]},"references-count":42,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["ijms252011075"],"URL":"https:\/\/doi.org\/10.3390\/ijms252011075","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,15]]}}}