Iron-sulfur cluster binding by mitochondrial monothiol glutaredoxin-1 of trypanosoma brucei

• Verfasst von: Manta, Bruno [VerfasserIn]
• Verfasst von: Pavan, Carlo [VerfasserIn]
• Verfasst von: Sturlese, Mattia [VerfasserIn]
• Verfasst von: Medeiros, Andrea [VerfasserIn]
• Verfasst von: Crispo, Martina [VerfasserIn]
• Verfasst von: Berndt, Carsten [VerfasserIn]
• Verfasst von: Krauth-Siegel, Renate [VerfasserIn]
• Verfasst von: Bellanda, Massimo [VerfasserIn]
• Verfasst von: Comini, Marcelo A. [VerfasserIn]
• Titel: Iron-sulfur cluster binding by mitochondrial monothiol glutaredoxin-1 of trypanosoma brucei
• Titelzusatz: molecular basis of iron-sulfur cluster coordination and relevance for parasite infectivity
• Verf.angabe: Bruno Manta, Carlo Pavan, Mattia Sturlese, Andrea Medeiros, Martina Crispo, Carsten Berndt, R. Luise Krauth-Siegel, Massimo Bellanda, and Marcelo A. Comini
• E-Jahr: 2013
• Jahr: 9 August 2013
• Umfang: 18 S.
• Teil: volume:19
• Teil: year:2013
• Teil: number:7
• Teil: month:09
• Teil: pages:665-682
• Teil: extent:18
• Fussnoten: Gesehen am 22.06.2021
• Titel Quelle: Enthalten in: Antioxidants & redox signaling
• Ort Quelle: Larchmont, NY : Liebert, 1999
• Jahr Quelle: 2013
• Band/Heft Quelle: 19(2013), 7 vom: Sept., Seite 665-682
• ISSN Quelle: 1557-7716
• DOI: doi:10.1089/ars.2012.4859
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1761023845

Abstract

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.