Honbou K, Suzuki NN, Horiuchi M, Niki T, Taira T, Ariga H, Inagaki F. The crystal structure of DJ-1, a protein related to male fertility and Parkinson's disease. J Biol Chem. 2003 Aug 15;278(33):31380-4. PubMed.

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  1. From the standpoint of someone who is interested in oxidative stress signaling, the crystal structure raises several interesting possibilities. First, the conversion of cys-53 to a cys-sulfinic acid is reminiscent of the change that occurs in the prokaryotic transcription factor OxyR in response to hydroperoxide in bacteria. In that scheme, hydrogen peroxide modifies cys-199. This leads to a conformational change in the OxyR protein, which allows transcription of genes that compensate for oxidative stress. OxyR is thus the prototypic redox sensor. It is possible that DJ-1 also functions as a redox sensor.

    If peroxide levels drift above a homeostatic threshold, then cys53 gets converted to a sulfinic acid, leading to a conformational change and an activation of protease activity. One consequence of this activation would be to activate the androgen receptor or other transcription factors as a compensatory response. Another possibility is that DJ-1 controls not survival, but executes death, and that DJ-1, like caspases or calpains, is involved in selective proteolytic cleavage of substrates that ensure cell death.

    I favor the scenario in which DJ-1 is part of a protective pathway because of the genetic association with PD (and the response to toxicants in sperm); however, it is possible that mutations associated with PD decrease the threshold for DJ-1 activation and thereby increase vulnerability of nigral neurons to trigger events irreversibly associated with death.

    View all comments by Rajiv Ratan

  2. These papers are important steps forward to clarify the exact function of DJ-1, and, in turn, to promote understanding of the pathogenesis of DJ-1-related and of classical Parkinson's disease.

    These studies report the crystal structure of human DJ-1, identifying a putative active site, and comparing the structure with other members of the DJ-1-ThiJ-PfpI superfamily.

    An important finding in both studies is that DJ-1 is able to form dimers. Moreover, both studies confirm that the residue mutated in the PARK7 patients (L166) is located in an a-helix region, and that the mutation (L166P) appears to induce severe structural consequences. If other disease-linked missense mutations in DJ-1 are identified, they will pinpoint other functionally important domains. This would complement the biochemical and structural biology studies in the common effort to elucidate the role of this fascinating protein.

    View all comments by Vincenzo Bonifati

  3. The solution of the crystal structure of DJ-1 is indeed a great step forward, and the localisation of the L166P mutation is very helpful. Vincenzo Bonifati and colleagues suggested that this might be in a helical region in their Science paper, and it is reassuring to see the crystal structure agree with their predictions.

    A word of caution is warranted, however, about the interpretation of structural data in terms of what it tells us about function. As Tom Fagan points out, a catalytic triad has not been identified. Crucially, the idea that DJ1 might have protease (or kinase) activity still needs to be tested.
    This leads to a bigger issue. Numerous cases are known of structural homologues with low sequence homology, and of many sequence homologues, all of which have very diverse functions. Therefore, arguing for function based on sequence or structural homology is weak. A key experiment now is to purify DJ1 and assay for a variety of possible activities, a list that I suggest should include: protease (caspase-like and serine protease-like), kinase, amidotransferase, and chaperone activity. Not an inconsiderable task, but potentially useful.

    Finally, the cys53ala mutation is a very useful observation, but I wish the paper could have shown the data for that. There are three conserved cysteines in DJ1. Do all of them sense redox states? A systematic analysis is warranted.

    View all comments by Mark Cookson

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