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Polymerization of Oxidized DJ-1 via Noncovalent and Covalent Binding: Significance of Disulfide Bond Formation.

ABSTRACT: The reactive cysteine residue at position 106 (Cys106) of DJ-1 is preferentially oxidized under oxidative stress, generating oxidized DJ-1 (oxDJ-1). Oxidation of Cys106 to sulfinic acid changes the biologic action of DJ-1 and increases its cytoprotective properties. The similar activation step is known in peroxiredoxins (Prxs), in which oxidation of reactive Cys to sulfinic acid induces polymerization of Prxs and changes its enzyme characteristic from peroxidase to molecular chaperone. In the present study, oxDJ-1 was prepared and its polymerization and related amino acid residues were investigated. We found that oxDJ-1 formed a characteristic polymer with disulfide bonds and with noncovalent and covalent binding other than disulfide. The physiological concentration of glutathione resolved the polymer form of oxDJ-1, and glutathionylation of other two Cys residues, such as Cys 46 and 53, was detected. Mutant analysis indicated the necessity not only of Cys106 but also of Cys46 for the polymer formation. The cellular experiment demonstrated that the electrophilic quinone treatment induced a high-molecular-weight complex containing oxDJ-1. Dynamic polymerization of oxDJ-1 with a ring and a stacked structure was observed by an atomic force microscope. Collectively, these results clearly demonstrated the characteristic polymer formation of oxDJ-1 with a disulfide bond and noncovalent and covalent binding other than disulfide, which might be related to the biologic function of oxDJ-1.

SUBMITTER: Kobayashi M

PROVIDER: S-EPMC6648325 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Polymerization of Oxidized DJ-1 via Noncovalent and Covalent Binding: Significance of Disulfide Bond Formation.

Kobayashi Mayuka M Muramatsu Kana K Haruyama Takamitsu T Uesugi Haruka H Kikuchi Ai A Konno Hiroki H Noguchi Noriko N Saito Yoshiro Y

ACS omega 20190603 6

The reactive cysteine residue at position 106 (Cys106) of DJ-1 is preferentially oxidized under oxidative stress, generating oxidized DJ-1 (oxDJ-1). Oxidation of Cys106 to sulfinic acid changes the biologic action of DJ-1 and increases its cytoprotective properties. The similar activation step is known in peroxiredoxins (Prxs), in which oxidation of reactive Cys to sulfinic acid induces polymerization of Prxs and changes its enzyme characteristic from peroxidase to molecular chaperone. In the pr ...[more]

PMID: 31460051

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Project description:The protein secretory pathway must maintain homoeostasis while producing a wide assortment of proteins in different conditions. It is also used extensively to produce many useful proteins in biotechnology. As such, secretory pathway dysfunction can be highly detrimental to the cell, resulting in the molecular basis for many human diseases, and can drastically inhibit product titers in biochemical production. Because the secretory pathway is a highly-integrated, multi-organelle system, dysfunction can happen at many levels and dissecting the root cause can be challenging. To better understand some of these dysfunctions, we measured multiple systems-level states of the cell (physiology, transcriptome, metabolism) while secreting a small protein (insulin precursor) or a large protein (?-amylase). This was carried out in the presence and absence of HAC1, a key transcription factor in maintaining secretory homeostasis. Clear trends in cellular stress were apparent across multiple data resulting from our perturbations. In particular, processes involving (1) degradation of protein / recycling amino acids, (2) overall transcription/translation repression, and (3) oxidative stress. Apparent runaway oxidative radical production was explained by a thermodynamic model that we put forward for disulfide formation in the endoplasmic reticulum. This model predicts that balancing the relative rates of protein folding and disulfide bond formation are key to easing oxidative stress. These predictions have direct implications in how to engineer a broad range of recombinant proteins for secretion and provide potential hypotheses for the root causes of several secretory-associated diseases. Yeast strains were constructed that produce and secrete (a) IP or (b) ?-amylase and were compared to yeast strains containing (c) an empty vector in both wild-type and HAC1 deletion backgrounds. These strains are named WN (WT with empty vector), WI (WT secreting IP), WA (WT secreting ?-amylase), dN (?hac1 with empty vector), dI (?hac1 secreting IP), and dA (?hac1 secreting ?-amylase). Strains were characterized in batch fermentation and samples were taken in mid-exponential phase. Triplicate fermentations were carried out for each strain.

Dataset Information

Polymerization of Oxidized DJ-1 via Noncovalent and Covalent Binding: Significance of Disulfide Bond Formation.

Publications

Polymerization of Oxidized DJ-1 via Noncovalent and Covalent Binding: Significance of Disulfide Bond Formation.

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