1. The C terminus of DJ-1 determines its homodimerization, MGO detoxification activity and suppression of ferroptosis
- Author
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Ji Cao, Hong Zhu, Xiaobing Chen, Meidan Ying, Li Jiang, Qiaojun He, Chengyong Du, Haiying Zhu, Qian Wu, and Bo Yang
- Subjects
0301 basic medicine ,Protein Deglycase DJ-1 ,Article ,Mouse embryonic fibroblast ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Animals ,Ferroptosis ,Humans ,Pharmacology (medical) ,Amino Acid Sequence ,Pharmacology ,chemistry.chemical_classification ,Chemistry ,C-terminus ,Point mutation ,Methylglyoxal ,HEK 293 cells ,General Medicine ,Pyruvaldehyde ,Amino acid ,Cell biology ,HEK293 Cells ,030104 developmental biology ,Enzyme ,030220 oncology & carcinogenesis ,Protein Multimerization - 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.
- Published
- 2020