Iron-sulfur cluster binding by mitochondrial monothiol glutaredoxin-1 of trypanosoma brucei: molecular basis of iron-sulfur cluster coordination and relevance for parasite infectivity
Aims: Monothiol glutaredoxins (1-C-Grxs) are small proteins linked to the cellular iron and redox metabolism. Trypanosoma brucei brucei, model organism for human African trypanosomiasis, expresses three 1-C-Grxs. 1-C-Grx1 is a highly abundant mitochondrial protein capable to bind an iron-sulfur clus...
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| Hauptverfasser: | , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
9 August 2013
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| In: |
Antioxidants & redox signaling
Year: 2013, Jahrgang: 19, Heft: 7, Pages: 665-682 |
| ISSN: | 1557-7716 |
| DOI: | 10.1089/ars.2012.4859 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1089/ars.2012.4859 Verlag, lizenzpflichtig, Volltext: https://www.liebertpub.com/doi/10.1089/ars.2012.4859 
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| Verfasserangaben: | Bruno Manta, Carlo Pavan, Mattia Sturlese, Andrea Medeiros, Martina Crispo, Carsten Berndt, R. Luise Krauth-Siegel, Massimo Bellanda, and Marcelo A. Comini |
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| 245 | 1 | 0 | |a Iron-sulfur cluster binding by mitochondrial monothiol glutaredoxin-1 of trypanosoma brucei |b molecular basis of iron-sulfur cluster coordination and relevance for parasite infectivity |c Bruno Manta, Carlo Pavan, Mattia Sturlese, Andrea Medeiros, Martina Crispo, Carsten Berndt, R. Luise Krauth-Siegel, Massimo Bellanda, and Marcelo A. Comini |
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| 520 | |a Aims: Monothiol glutaredoxins (1-C-Grxs) are small proteins linked to the cellular iron and redox metabolism. Trypanosoma brucei brucei, model organism for human African trypanosomiasis, expresses three 1-C-Grxs. 1-C-Grx1 is a highly abundant mitochondrial protein capable to bind an iron-sulfur cluster (ISC) in vitro using glutathione (GSH) as cofactor. We here report on the functional and structural analysis of 1-C-Grx1 in relation to its ISC-binding properties. Results: An N-terminal extension unique to 1-C-Grx1 from trypanosomatids affects the oligomeric structure and the ISC-binding capacity of the protein. The active-site Cys104 is essential for ISC binding, and the parasite-specific glutathionylspermidine and trypanothione can replace GSH as the ligands of the ISC. Interestingly, trypanothione forms stable protein-free ISC species that in vitro are incorporated into the dithiol T. brucei 2-C-Grx1, but not 1-C-Grx1. Overexpression of the C104S mutant of 1-C-Grx1 impairs disease progression in a mouse model. The structure of the Grx-domain of 1-C-Grx1 was solved by nuclear magnetic resonance spectroscopy. Despite the fact that several residues—which in other 1-C-Grxs are involved in the noncovalent binding of GSH—are conserved, different physicochemical approaches did not reveal any specific interaction between 1-C-Grx1 and free thiol ligands. Innovation: Parasite Grxs are able to coordinate an ISC formed with trypanothione, suggesting a new mechanism of ISC binding and a novel function for the parasite-specific dithiol. The first 3D structure and in vivo relevance of a 1-C-Grx from a pathogenic protozoan are reported. Conclusion:T. brucei 1-C-Grx1 is indispensable for mammalian parasitism and utilizes a new mechanism for ISC binding. Antioxid. Redox Signal. 19, 665-682. | ||
| 700 | 1 | |a Pavan, Carlo |e VerfasserIn |4 aut | |
| 700 | 1 | |a Sturlese, Mattia |e VerfasserIn |4 aut | |
| 700 | 1 | |a Medeiros, Andrea |e VerfasserIn |4 aut | |
| 700 | 1 | |a Crispo, Martina |e VerfasserIn |4 aut | |
| 700 | 1 | |a Berndt, Carsten |e VerfasserIn |4 aut | |
| 700 | 1 | |a Krauth-Siegel, Renate |e VerfasserIn |0 (DE-588)1050022335 |0 (DE-627)783217390 |0 (DE-576)404300200 |4 aut | |
| 700 | 1 | |a Bellanda, Massimo |e VerfasserIn |4 aut | |
| 700 | 1 | |a Comini, Marcelo A. |e VerfasserIn |4 aut | |
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