Identification of the recognition sequence and target proteins for DJ‐1 protease

Mitsugi, Hitomi; Niki, Takeshi; Takahashi-Niki, Kazuko; Tanimura, Kyoko; Yoshizawa‐Kumagaye, Kumiko; Tsunemi, Masahiko; Iguchi‐Ariga, Sanae M.M.; Ariga, Hiroyoshi

doi:10.1016/j.febslet.2013.06.032

Cited by 18 publications

(18 citation statements)

References 37 publications

(49 reference statements)

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“…It has been also shown that Cterminal truncated forms of DJ-1 have increased protease activity, while wild-type DJ-1 does not. This may be in line with our observations in this study, suggesting a critical role in intermonomer interactions between the C-terminal and His126 region [57]. On the basis of the analysis of DJ-1 crystal structures, Wilson et al suggested that the formation of over-oxidized Cys106 is sterically disfavored by the surrounding residues, particularly the Cβ atom of His126 [58].…”

Section: Higher Thermal Stability Of Oxidized and Over-oxidized Dj-1 supporting

confidence: 92%

Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease

Kingsford-Adaboh

Zhu²,

Jójárt

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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DJ-1 (PARK7) is a multifunctional protein linked to the onset and progression of a number of diseases, most of which are associated with high oxidative stress. The Cys106 of DJ-1 is unusually reactive and thus sensitive to oxidation, and due to high oxidative stress it was observed to be in various oxidized states in disease condition. The oxidation state of Cys106 of DJ-1 is believed to determine the specific functions of the protein in normal and disease conditions. Here we report molecular dynamics simulation and biophysical experimental studies on DJ-1 in reduced (Cys106, S), oxidized (Cys106, SO), and over-oxidized (Cys106, SO) states. To simulate the different oxidation states of Cys106 in DJ-1, AMBER related force field parameters were developed and reported for 3-sulfinoalanine and cysteine sulfonic acid. Our studies found that the overall structure of DJ-1 in different oxidation states was similar globally, while it differed locally significantly, which have implications on its stability, function and its link to disease on-set. Importantly, the results suggest that over-oxidation may trigger loss of functions due to local structural modification in the Cys106 containing pocket of DJ-1 and structurally destabilize the dimeric state of DJ-1, which is believed to be its bioactive conformation. Such loss of functions would result in reduced ability of DJ-1 to protect from oxidative stress insults and may lead to increased progression of disease.

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Section: Higher Thermal Stability Of Oxidized and Over-oxidized Dj-1 supporting

confidence: 92%

Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease

Kingsford-Adaboh

Zhu²,

Jójárt

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…6), indicating that DJ-1 is able to activate c-Raf without other factors under these conditions. Although DJ-1 has several enzymatic activities, including protease (37)(38)(39)(40) and glyoxalase activities (41)(42)(43)(44), there is no report showing that DJ-1 is a protein kinase and that DJ-1 has a structural motif for kinase (3)(4)(5). These results therefore suggest that DJ-1 enhances self-phosphorylation activity of c-Raf without a role as kinase.…”

Section: Discussionmentioning

confidence: 79%

Epidermal Growth Factor-dependent Activation of the Extracellular Signal-regulated Kinase Pathway by DJ-1 Protein through Its Direct Binding to c-Raf Protein

Takahashi-Niki

Kato-Ose

Murata

et al. 2015

Journal of Biological Chemistry

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Background: DJ-1 is a ras-cooperating oncogene and activates the ERK pathway. Results: DJ-1 directly binds to the kinase domain of c-Raf to stimulate its self-phosphorylation, followed by phosphorylation of MEK and ERK1/2 in EGF-treated cells. Conclusion: DJ-1 activates the ERK pathway by directly binding to c-Raf but not to Ras. Significance: DJ-1 is a positive regulator for the EGF/Ras/ERK pathway.

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“…Several studies have suggested the protease activity of DJ-1; however, this protease activity is very low. (30) Both the cleavage of the C-terminal helix under oxidative stress and the increase in the protease activity of the C-terminal helix deletion mutant have been reported. (30) However, the physiological role of DJ-1 as a cysteine protease is still under debate.…”

Section: Protein Characterization Of Dj-1mentioning

confidence: 99%

“…(30) Both the cleavage of the C-terminal helix under oxidative stress and the increase in the protease activity of the C-terminal helix deletion mutant have been reported. (30) However, the physiological role of DJ-1 as a cysteine protease is still under debate. In addition, the tertiary structure of DJ-1 was similar to that of E. coli heat shock protein HSP31, a structural homolog of PH1704 protease.…”

Section: Protein Characterization Of Dj-1mentioning

confidence: 99%

Oxidized DJ-1 as a possible biomarker of Parkinson’s disease

Saito

2014

J. Clin. Biochem. Nutr.

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Parkinson’s disease is a progressive, age-related, neurodegenerative disorder, and oxidative stress is an important mediator in its pathogenesis. DJ-1 is a causative gene of a familial form of Parkinson’s disease, namely PARK7, and plays a significant role in antioxidative defense to protect the cells from oxidative stress. DJ-1 undergoes preferential oxidation at the cysteine residue at position 106, Cys-106, under oxidative stress. The critical role of Cys-106 in the biological function of DJ-1 has been demonstrated, and recent studies indicate that DJ-1 acts as a sensor of oxidative stress by regulating the gene expression of antioxidative defense. Specific antibodies against Cys-106-oxidized DJ-1 have been developed, and the generation of oxidized DJ-1 in cellular and animal models of Parkinson’s disease has been investigated. This review focuses on the role of DJ-1 in antioxidative defense and the importance of oxidizable Cys-106 in its function. The significance of the identification of early-phase Parkinson’s disease biomarkers and the nature of oxidized DJ-1 as a biomarker for Parkinson’s disease are discussed here.

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Identification of the recognition sequence and target proteins for DJ‐1 protease

Cited by 18 publications

References 37 publications

Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease

Structural features of human DJ-1 in distinct Cys106 oxidative states and their relevance to its loss of function in disease

Epidermal Growth Factor-dependent Activation of the Extracellular Signal-regulated Kinase Pathway by DJ-1 Protein through Its Direct Binding to c-Raf Protein

Oxidized DJ-1 as a possible biomarker of Parkinson’s disease

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