The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein.
DJ-1 has been reported to have chaperone activity by preventing the aggregation of some proteins, and by structural analogy to Hsp31. The L166P mutation has been linked to a familial early onset form of Parkinson's disease (PD). Since the aggregation of alpha-synuclein is believed to be a critical step in the etiology of PD, we have investigated the interaction of wild-type DJ-1 and its oxidized forms with alpha-synuclein. Native (unoxidized) DJ-1 did not inhibit alpha-synuclein fibrillation, and no evidence for stable interactions between alpha-synuclein and native DJ-1 was observed. However, DJ-1 is very susceptible to oxidation by the addition of two oxygen atoms to form the sulfinic acid of Cys106 (2O DJ-1) (no 1O oxidized state is detectable). 2O DJ-1 was readily prepared by the addition of H(2)O(2) at concentrations up to a 20-fold molar excess. The oxidation of Cys106 to the sulfinic acid had minimal effect on the structural properties of DJ-1. However, 2O DJ-1 was very effective in preventing the fibrillation of alpha-synuclein, and only this form of DJ-1 appears to have significant anti-aggregation properties against alpha-synuclein. Further oxidation of DJ-1 leads to loss of some secondary structure, and to loss of the ability to inhibit alpha-synuclein fibrillation. Our observations confirm the suggestion that DJ-1 may act as an oxidative-stress-induced chaperone to prevent alpha-synuclein fibrillation. Since oxidative stress has been associated with PD, this observation may explain why mutations of DJ-1 could be a contributing factor in PD, and also indicates that excess oxidative stress could also lead to enhanced alpha-synuclein aggregation and hence PD.
Zhou
Wenbo
W
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA.
Zhu
Min
M
Wilson
Mark A
MA
Petsko
Gregory A
GA
Fink
Anthony L
AL
D000818:Animals; D002942:Circular Dichroism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D013058:Mass Spectrometry; D018832:Molecular Chaperones / Q000737:chemistry* / Q000378:metabolism; D015513:Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D011487:Protein Conformation; D000071617:Protein Deglycase DJ-1; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure
D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D015513:Oncogene Proteins; D051844:alpha-Synuclein; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D010100:Oxygen