Structure of Cu(I)-Bound DJ-1 Reveals a Biscysteinate Metal Binding Site at the Homodimer Interface: Insights into Mutational Inactivation of DJ-1 in Parkinsonism

Puno, M. Rhyan; Patel, Nisha; Møller, Simon Geir; Robinson, Carol V.; Moody, P.C.E.; Odell, Mark

doi:10.1021/ja406010m

Cited by 19 publications

(22 citation statements)

References 35 publications

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“…The latter metal binding site is located between the two Cys-53 residues that face each other. Very recently, the structure of a Cu(I)-DJ-1 complex, resulting from the incubation of the protein with a Cu(I)-glutathione complex, has been reported (32). In agreement with our data, the authors describe the presence of a Cu(I) ion bound at the dimer interface, whereas, at variance with us, they do not observe any metal ion bound to Cys-106.…”

Section: Resultssupporting

confidence: 92%

“…Although we identified site 2 as an actual Cu(I) binding site, we suggest that copper binding site 1, involving Cys-106, is the key site that allows the transfer of the metal to SOD1 under critical conditions. The latter function ascribed to the Cys-106 copper binding site could coexist with the function already suggested for the Cys-53 metal binding site (22,32).…”

Section: Discussionmentioning

confidence: 56%

“…We may therefore conclude from the absence of a functional effect that the Cu(I) binding site located between the two Cys-53 residues in the DJ-1 dimer may be related to a function different from the one described here (22,32). We did not proceed further in the investigation of the specific function supported by this Cu(I) binding site, although it may be the one described by Bjorkblom et al (22) (i.e.…”

Section: Discussionmentioning

confidence: 69%

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DJ-1 Is a Copper Chaperone Acting on SOD1 Activation

Girotto

Cendron

Bisaglia

et al. 2014

Journal of Biological Chemistry

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Background: DJ-1 and SOD1 are proteins involved in Parkinson disease and ALS, respectively. Results: A novel DJ-1 copper binding site is characterized together with its ability to activate SOD1 through copper transfer. Conclusion:We have identified a putative role for DJ-1 as a copper chaperone. Significance: Alterations of the coordination of the copper ion in DJ-1 may affect neurodegenerative etiopathogenesis.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 69%

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DJ-1 Is a Copper Chaperone Acting on SOD1 Activation

Girotto

Cendron

Bisaglia

et al. 2014

Journal of Biological Chemistry

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“…Notably DJ-1 has been shown to directly regulate SOD1 activity 11 . Cu (II) ATSM delivery in vivo has been reported to increase mutated SOD1 activity in the brain 13 , but to date, only experiments without the use of cells have established that copper enriched DJ-1 directly increases SOD1 activity 11,40,41 . In this study, we have identified increased DJ-1 and SOD1 protein interactions in HCASMC treated with Cu (II) ATSM, providing a possible mechanism by which SOD1 activity may be increased acutely.…”

Section: Discussionmentioning

confidence: 99%

Cardioprotective effects of Cu(II)ATSM in human vascular smooth muscle cells and cardiomyocytes mediated by Nrf2 and DJ-1

Srivastava

Blower

Aubdool

et al. 2016

Sci Rep

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Cu(II)ATSM was developed as a hypoxia sensitive positron emission tomography agent. Recent reports have highlighted the neuroprotective properties of Cu(II)ATSM, yet there are no reports that it confers cardioprotection. We demonstrate that Cu(II)ATSM activates the redox-sensitive transcription factor Nrf2 in human coronary artery smooth muscle cells (HCASMC) and cardiac myocytes (HCM), leading to upregulation of antioxidant defense enzymes. Oral delivery of Cu(II)ATSM in mice induced expression of the Nrf2-regulated enzymes in the heart and aorta. In HCASMC, Cu(II)ATSM increased expression of the Nrf2 stabilizer DJ-1, and knockdown of Nrf2 or DJ-1 attenuated Cu(II)ATSM-mediated heme oxygenase-1 and NADPH quinone oxidoreductase-1 induction. Pre-treatment of HCASMC with Cu(II)ATSM protected against the pro-oxidant effects of angiotensin II (Ang II) by attenuating superoxide generation, apoptosis, proliferation and increases in intracellular calcium. Notably, Cu(II)ATSM-mediated protection against Ang II-induced HCASMC apoptosis was diminished by Nrf2 knockdown. Acute treatment with Cu(II)ATSM enhanced the association of DJ-1 with superoxide dismutase-1 (SOD1), paralleled by significant increases in intracellular Cu(II) levels and SOD1 activity. We describe a novel mechanism by which Cu(II)ATSM induces Nrf2-regulated antioxidant enzymes and protects against Ang II-mediated HCASMC dysfunction via activation of the Nrf2/DJ-1 axis. Cu(II)ATSM may provide a therapeutic strategy for cardioprotection via upregulation of antioxidant defenses.

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“…In fact, copper is more toxic to E. coli cells under anaerobic conditions than under aerobic conditions (9,10), indicating that other cellular mechanisms could be responsible for copper toxicity. Because copper needs only two thiol groups to form a linear biscysteinate coordination in proteins (11), excess copper in cells may directly compete with iron or iron-sulfur cluster binding sites in proteins to disrupt iron-sulfur clusters (12,13) or block ironsulfur cluster biogenesis (14)(15)(16). Since iron-sulfur proteins are involved in diverse and vital physiological processes ranging from energy metabolism to DNA replication and repair (17,18), inactivation of iron-sulfur proteins by copper will have a broad impact on multiple physiological functions in cells.…”

mentioning

confidence: 99%

Anaerobic Copper Toxicity and Iron-Sulfur Cluster Biogenesis in Escherichia coli

Tan

Yang

Tang

et al. 2017

Appl Environ Microbiol

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While copper is an essential trace element in biology, pollution of groundwater from copper has become a threat to all living organisms. Cellular mechanisms underlying copper toxicity, however, are still not fully understood. Previous studies have shown that iron-sulfur proteins are among the primary targets of copper toxicity in Escherichia coli under aerobic conditions. Here, we report that, under anaerobic conditions, iron-sulfur proteins in E. coli cells are even more susceptible to copper in medium. Whereas addition of 0.2 mM copper(II) chloride to LB (Luria-Bertani) medium has very little or no effect on iron-sulfur proteins in wild-type E. coli cells under aerobic conditions, the same copper treatment largely inactivates iron-sulfur proteins by blocking iron-sulfur cluster biogenesis in the cells under anaerobic conditions. Importantly, proteins that do not have iron-sulfur clusters (e.g., fumarase C and cysteine desulfurase) in E. coli cells are not significantly affected by copper treatment under aerobic or anaerobic conditions, indicating that copper may specifically target iron-sulfur proteins in cells. Additional studies revealed that E. coli cells accumulate more intracellular copper under anaerobic conditions than under aerobic conditions and that the elevated copper content binds to the iron-sulfur cluster assembly proteins IscU and IscA, which effectively inhibits iron-sulfur cluster biogenesis. The results suggest that the copper-mediated inhibition of iron-sulfur proteins does not require oxygen and that iron-sulfur cluster biogenesis is the primary target of anaerobic copper toxicity in cells.IMPORTANCE Copper contamination in groundwater has become a threat to all living organisms. However, cellular mechanisms underlying copper toxicity have not been fully understood up to now. The work described here reveals that iron-sulfur proteins in Escherichia coli cells are much more susceptible to copper in medium under anaerobic conditions than they are under aerobic conditions. Under anaerobic conditions, E. coli cells accumulate excess intracellular copper, which specifically targets iron-sulfur proteins by blocking iron-sulfur cluster biogenesis. Since iron-sulfur proteins are involved in diverse and vital physiological processes, inhibition of ironsulfur cluster biogenesis by copper disrupts multiple cellular functions and ultimately inhibits cell growth. The results from this study illustrate a new interplay between intracellular copper toxicity and iron-sulfur cluster biogenesis in bacterial cells under anaerobic conditions.

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Structure of Cu(I)-Bound DJ-1 Reveals a Biscysteinate Metal Binding Site at the Homodimer Interface: Insights into Mutational Inactivation of DJ-1 in Parkinsonism

Cited by 19 publications

References 35 publications

DJ-1 Is a Copper Chaperone Acting on SOD1 Activation

DJ-1 Is a Copper Chaperone Acting on SOD1 Activation

Cardioprotective effects of Cu(II)ATSM in human vascular smooth muscle cells and cardiomyocytes mediated by Nrf2 and DJ-1

Anaerobic Copper Toxicity and Iron-Sulfur Cluster Biogenesis in Escherichia coli

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