The lineage-specific, intrinsically disordered N-terminal extension of monothiol glutaredoxin 1 from trypanosomes contains a regulatory region

Abstract Glutaredoxins (Grx) are small proteins conserved throughout all the kingdoms of life that are engaged in a wide variety of biological processes and share a common thioredoxin-fold. Among them, class II Grx are redox-inactive proteins involved in iron-sulfur (FeS) metabolism. They contain a...

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Autores principales:	Mattia Sturlese, Bruno Manta, Andrea Bertarello, Mariana Bonilla, Moreno Lelli, Barbara Zambelli, Karin Grunberg, Stefano Mammi, Marcelo A. Comini, Massimo Bellanda
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Grx C1 Intrinsically Disordered Regions Residual Dipolar Couplings (RDCs) Multiangle Light Scattering (MALS) Limited Proteolysis Assays Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d2ac22c55c0e492ba0d1f44f23cfdd25
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spelling	oai:doaj.org-article:d2ac22c55c0e492ba0d1f44f23cfdd252021-12-02T15:09:09ZThe lineage-specific, intrinsically disordered N-terminal extension of monothiol glutaredoxin 1 from trypanosomes contains a regulatory region10.1038/s41598-018-31817-42045-2322https://doaj.org/article/d2ac22c55c0e492ba0d1f44f23cfdd252018-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-31817-4https://doaj.org/toc/2045-2322Abstract Glutaredoxins (Grx) are small proteins conserved throughout all the kingdoms of life that are engaged in a wide variety of biological processes and share a common thioredoxin-fold. Among them, class II Grx are redox-inactive proteins involved in iron-sulfur (FeS) metabolism. They contain a single thiol group in their active site and use low molecular mass thiols such as glutathione as ligand for binding FeS-clusters. In this study, we investigated molecular aspects of 1CGrx1 from the pathogenic parasite Trypanosoma brucei brucei, a mitochondrial class II Grx that fulfills an indispensable role in vivo. Mitochondrial 1CGrx1 from trypanosomes differs from orthologues in several features including the presence of a parasite-specific N-terminal extension (NTE) whose role has yet to be elucidated. Previously we have solved the structure of a truncated form of 1CGrx1 containing only the conserved glutaredoxin domain but lacking the NTE. Our aim here is to investigate the effect of the NTE on the conformation of the protein. We therefore solved the NMR structure of the full-length protein, which reveals subtle but significant differences with the structure of the NTE-less form. By means of different experimental approaches, the NTE proved to be intrinsically disordered and not involved in the non-redox dependent protein dimerization, as previously suggested. Interestingly, the portion comprising residues 65–76 of the NTE modulates the conformational dynamics of the glutathione-binding pocket, which may play a role in iron-sulfur cluster assembly and delivery. Furthermore, we disclosed that the class II-strictly conserved loop that precedes the active site is critical for stabilizing the protein structure. So far, this represents the first communication of a Grx containing an intrinsically disordered region that defines a new protein subgroup within class II Grx.Mattia SturleseBruno MantaAndrea BertarelloMariana BonillaMoreno LelliBarbara ZambelliKarin GrunbergStefano MammiMarcelo A. CominiMassimo BellandaNature PortfolioarticleGrx C1Intrinsically Disordered RegionsResidual Dipolar Couplings (RDCs)Multiangle Light Scattering (MALS)Limited Proteolysis AssaysMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-14 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Grx C1 Intrinsically Disordered Regions Residual Dipolar Couplings (RDCs) Multiangle Light Scattering (MALS) Limited Proteolysis Assays Medicine R Science Q
spellingShingle	Grx C1 Intrinsically Disordered Regions Residual Dipolar Couplings (RDCs) Multiangle Light Scattering (MALS) Limited Proteolysis Assays Medicine R Science Q Mattia Sturlese Bruno Manta Andrea Bertarello Mariana Bonilla Moreno Lelli Barbara Zambelli Karin Grunberg Stefano Mammi Marcelo A. Comini Massimo Bellanda The lineage-specific, intrinsically disordered N-terminal extension of monothiol glutaredoxin 1 from trypanosomes contains a regulatory region
description	Abstract Glutaredoxins (Grx) are small proteins conserved throughout all the kingdoms of life that are engaged in a wide variety of biological processes and share a common thioredoxin-fold. Among them, class II Grx are redox-inactive proteins involved in iron-sulfur (FeS) metabolism. They contain a single thiol group in their active site and use low molecular mass thiols such as glutathione as ligand for binding FeS-clusters. In this study, we investigated molecular aspects of 1CGrx1 from the pathogenic parasite Trypanosoma brucei brucei, a mitochondrial class II Grx that fulfills an indispensable role in vivo. Mitochondrial 1CGrx1 from trypanosomes differs from orthologues in several features including the presence of a parasite-specific N-terminal extension (NTE) whose role has yet to be elucidated. Previously we have solved the structure of a truncated form of 1CGrx1 containing only the conserved glutaredoxin domain but lacking the NTE. Our aim here is to investigate the effect of the NTE on the conformation of the protein. We therefore solved the NMR structure of the full-length protein, which reveals subtle but significant differences with the structure of the NTE-less form. By means of different experimental approaches, the NTE proved to be intrinsically disordered and not involved in the non-redox dependent protein dimerization, as previously suggested. Interestingly, the portion comprising residues 65–76 of the NTE modulates the conformational dynamics of the glutathione-binding pocket, which may play a role in iron-sulfur cluster assembly and delivery. Furthermore, we disclosed that the class II-strictly conserved loop that precedes the active site is critical for stabilizing the protein structure. So far, this represents the first communication of a Grx containing an intrinsically disordered region that defines a new protein subgroup within class II Grx.
format	article
author	Mattia Sturlese Bruno Manta Andrea Bertarello Mariana Bonilla Moreno Lelli Barbara Zambelli Karin Grunberg Stefano Mammi Marcelo A. Comini Massimo Bellanda
author_facet	Mattia Sturlese Bruno Manta Andrea Bertarello Mariana Bonilla Moreno Lelli Barbara Zambelli Karin Grunberg Stefano Mammi Marcelo A. Comini Massimo Bellanda
author_sort	Mattia Sturlese
title	The lineage-specific, intrinsically disordered N-terminal extension of monothiol glutaredoxin 1 from trypanosomes contains a regulatory region
title_short	The lineage-specific, intrinsically disordered N-terminal extension of monothiol glutaredoxin 1 from trypanosomes contains a regulatory region
title_full	The lineage-specific, intrinsically disordered N-terminal extension of monothiol glutaredoxin 1 from trypanosomes contains a regulatory region
title_fullStr	The lineage-specific, intrinsically disordered N-terminal extension of monothiol glutaredoxin 1 from trypanosomes contains a regulatory region
title_full_unstemmed	The lineage-specific, intrinsically disordered N-terminal extension of monothiol glutaredoxin 1 from trypanosomes contains a regulatory region
title_sort	lineage-specific, intrinsically disordered n-terminal extension of monothiol glutaredoxin 1 from trypanosomes contains a regulatory region
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/d2ac22c55c0e492ba0d1f44f23cfdd25
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The lineage-specific, intrinsically disordered N-terminal extension of monothiol glutaredoxin 1 from trypanosomes contains a regulatory region

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