Abstract
DJ-1 is a multifunctional protein associated with cancers and autosomal early-onset Parkinson disease. Besides the well-documented antioxidative stress activity, recent studies show that DJ-1 has deglycation enzymatic activity and anti-ferroptosis effect. It has been shown that DJ-1 forms the homodimerization, which dictates its antioxidative stress activity. In this study, we investigated the relationship between the dimeric structure of DJ-1 and its newly reported activities. In HEK293T cells with Flag-tagged and Myc-tagged DJ-1 overexpression, we performed deletion mutations and point mutations, narrowed down the most critical motif at the C terminus. We found that the deletion mutation of the last three amino acids at the C terminus of DJ-1 (DJ-1 ΔC3) disrupted its homodimerization with the hydrophobic L187 residue being of great importance for DJ-1 homodimerization. In addition, the ability in methylglyoxal (MGO) detoxification and deglycation was almost abolished in the mutation of DJ-1 ΔC3 and point mutant L187E compared with wild-type DJ-1 (DJ-1 WT). We also showed the suppression of erastin-triggered ferroptosis in DJ-1−/− mouse embryonic fibroblast cells was abolished by ΔC3 and L187E, but partially diminished by V51C. Thus, our results demonstrate that the C terminus of DJ-1 is crucial for its homodimerization, deglycation activity, and suppression of ferroptosis.
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Acknowledgements
This work was supported by grants from National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program”, China (2018ZX09711002 to HZ), the National Natural Science Foundation of China (No. 81773757 to MDY; No. 81402951 to JC), and Zhejiang Medical and Health Science and Technology Program (No. 2020384517 to CYD).
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JC, LJ, and XBC designed the research and wrote the paper; LJ, XBC, QW, HYZ, CYD performed the biochemical and cellular studies; JC, LJ, XBC, HZ, and MDY analyzed the results; JC, HZ, MDY, QJH, and BY directed the study.
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Jiang, L., Chen, Xb., Wu, Q. et al. The C terminus of DJ-1 determines its homodimerization, MGO detoxification activity and suppression of ferroptosis. Acta Pharmacol Sin 42, 1150–1159 (2021). https://doi.org/10.1038/s41401-020-00531-1
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DOI: https://doi.org/10.1038/s41401-020-00531-1
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