{"doi":"10.1089/ars.2012.4859","title":"Iron–Sulfur Cluster Binding by Mitochondrial Monothiol Glutaredoxin-1 of\n                    <i>Trypanosoma brucei</i>\n                    : Molecular Basis of Iron–Sulfur Cluster Coordination and Relevance for Parasite Infectivity","abstract":"<jats:p>\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Aims:</jats:italic>\n                    </jats:bold>\n                    Monothiol glutaredoxins (1\n                    <jats:italic toggle=\"yes\">-</jats:italic>\n                    C\n                    <jats:italic toggle=\"yes\">-</jats:italic>\n                    Grxs) are small proteins linked to the cellular iron and redox metabolism.\n                    <jats:italic toggle=\"yes\">Trypanosoma brucei brucei</jats:italic>\n                    , 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)\n                    <jats:italic toggle=\"yes\">in vitro</jats:italic>\n                    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.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Results:</jats:italic>\n                    </jats:bold>\n                    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\n                    <jats:italic toggle=\"yes\">in vitro</jats:italic>\n                    are incorporated into the dithiol\n                    <jats:italic toggle=\"yes\">T. brucei</jats:italic>\n                    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.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Innovation:</jats:italic>\n                    </jats:bold>\n                    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\n                    <jats:italic toggle=\"yes\">in vivo</jats:italic>\n                    relevance of a 1-C-Grx from a pathogenic protozoan are reported.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Conclusion:</jats:italic>\n                    </jats:bold>\n                    <jats:italic toggle=\"yes\">T. brucei</jats:italic>\n                    1-C-Grx1 is indispensable for mammalian parasitism and utilizes a new mechanism for ISC binding.\n                    <jats:italic toggle=\"yes\">Antioxid. Redox Signal</jats:italic>\n                    . 19, 665–682.\n                  </jats:p>","journal":"Antioxidants &amp; Redox Signaling","year":2013,"id":680042,"datarank":0.5641800173540344,"base_score":3.7612001156935624,"endowment":3.7612001156935624,"self_citation_contribution":0.5641800173540344,"citation_network_contribution":0.0,"self_endowment_contribution":0.5641800173540344,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":42,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1776812,"name":"Carlo Pavan","orcid":null,"position":1,"is_corresponding":false},{"id":1776815,"name":"Mattia Sturlese","orcid":null,"position":2,"is_corresponding":false},{"id":1776817,"name":"Andrea Medeiros","orcid":null,"position":3,"is_corresponding":false},{"id":831048,"name":"Martina Crispo","orcid":"0000-0002-9852-5563","position":4,"is_corresponding":false},{"id":1199016,"name":"Carsten Berndt","orcid":"0000-0001-8583-7966","position":5,"is_corresponding":false},{"id":1545367,"name":"R. Luise Krauth-Siegel","orcid":null,"position":6,"is_corresponding":false},{"id":1776820,"name":"Massimo Bellanda","orcid":null,"position":7,"is_corresponding":false},{"id":1146861,"name":"Marcelo A. Comini","orcid":"0000-0001-5000-1333","position":8,"is_corresponding":false},{"id":337478,"name":"Bruno Manta","orcid":"0000-0001-8366-8935","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Iron–Sulfur Cluster Binding by Mitochondrial Monothiol Glutaredoxin-1 of\n                    <i>Trypanosoma brucei</i>\n                    : Molecular Basis of Iron–Sulfur Cluster Coordination and Relevance for Parasite Infectivity","abstract":"<jats:p>\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Aims:</jats:italic>\n                    </jats:bold>\n                    Monothiol glutaredoxins (1\n                    <jats:italic toggle=\"yes\">-</jats:italic>\n                    C\n                    <jats:italic toggle=\"yes\">-</jats:italic>\n                    Grxs) are small proteins linked to the cellular iron and redox metabolism.\n                    <jats:italic toggle=\"yes\">Trypanosoma brucei brucei</jats:italic>\n                    , 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)\n                    <jats:italic toggle=\"yes\">in vitro</jats:italic>\n                    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.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Results:</jats:italic>\n                    </jats:bold>\n                    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\n                    <jats:italic toggle=\"yes\">in vitro</jats:italic>\n                    are incorporated into the dithiol\n                    <jats:italic toggle=\"yes\">T. brucei</jats:italic>\n                    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.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Innovation:</jats:italic>\n                    </jats:bold>\n                    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\n                    <jats:italic toggle=\"yes\">in vivo</jats:italic>\n                    relevance of a 1-C-Grx from a pathogenic protozoan are reported.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Conclusion:</jats:italic>\n                    </jats:bold>\n                    <jats:italic toggle=\"yes\">T. brucei</jats:italic>\n                    1-C-Grx1 is indispensable for mammalian parasitism and utilizes a new mechanism for ISC binding.\n                    <jats:italic toggle=\"yes\">Antioxid. Redox Signal</jats:italic>\n                    . 19, 665–682.\n                  </jats:p>","is_dataset_classified":null,"base_score":3.7612001156935624,"endowment":3.7612001156935624,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"23259530","pmcid":"PMC3739951","openalex_id":"https://openalex.org/W2031934718","authors":[],"funders":[{"funder_name":"European Commission","grant_id":"261323","title":"European Grid Initiative: Integrated Sustainable Pan-European Infrastructure for Researchers in Europe"},{"funder_name":"European Commission","grant_id":"261863","title":"NMR for Structural Biology"},{"funder_name":"European Commission","grant_id":"261572","title":"A worldwide e-Infrastructure for NMR and structural biology"}],"total_grants":3,"fwci":1.5787,"citation_percentile":0.82326962,"influential_citations":0,"citation_trend":[{"year":2012,"count":1},{"year":2013,"count":3},{"year":2014,"count":5},{"year":2015,"count":5},{"year":2016,"count":4},{"year":2017,"count":2},{"year":2018,"count":5},{"year":2019,"count":1},{"year":2020,"count":2},{"year":2021,"count":3},{"year":2022,"count":6},{"year":2023,"count":2},{"year":2024,"count":1},{"year":2026,"count":2}],"oa_status":"green","license":"other-oa","oa_locations":[{"url":"http://hdl.handle.net/11577/2574442","host_type":"repository"},{"url":"http://hdl.handle.net/11577/2574442","host_type":"repository"},{"url":"https://journals.sagepub.com/doi/pdf/10.1089/ars.2012.4859","host_type":"publisher"},{"url":"https://journals.sagepub.com/doi/full-xml/10.1089/ars.2012.4859","host_type":"publisher"},{"url":"https://doi.org/10.1089/ars.2012.4859","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/23259530","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/3739951","host_type":"repository"},{"url":"https://europepmc.org/articles/pmc3739951?pdf=render","host_type":""},{"url":"http://dx.doi.org/10.1089/ars.2012.4859","host_type":""},{"url":"https://dx.doi.org/10.1089/ars.2012.4859","host_type":""},{"url":"https://hdl.handle.net/11577/2574442","host_type":""},{"url":"http://europepmc.org/articles/PMC3739951","host_type":""}],"fields_of_study":["Metalloenzymes and iron-sulfur proteins","Trypanosoma species research and implications","Metal-Catalyzed Oxygenation Mechanisms","0301 basic medicine","0303 health sciences","03 medical and health sciences","Amino Acid Sequence","Animals","Catalytic Domain","Coenzymes","Consensus Sequence","Cysteine","Female","Glutaredoxins","Glutathione","Iron-Sulfur Proteins","Mice","Mice, Inbred BALB C","Mitochondria","Models, Molecular","Molecular Sequence Data","Nuclear Magnetic Resonance, Biomolecular","Parasitemia","Protein Binding","Protein Structure, Secondary","Protozoan Proteins","Trypanosoma brucei brucei","Trypanosomiasis, African"],"mesh_terms":["Amino Acid Sequence","Animals","Coenzymes","Cysteine","Female","Glutathione","Iron-Sulfur Proteins","Mice, Inbred BALB C","Mitochondria","Models, Molecular","Molecular Sequence Data","Protein Binding","Trypanosoma brucei brucei","Trypanosomiasis, African","Protozoan Proteins","Consensus Sequence","Protein Structure, Secondary","Parasitemia","Nuclear Magnetic Resonance, Biomolecular","Catalytic Domain","Mice","Glutaredoxins"],"keywords":["Glutaredoxin","Trypanosoma brucei","Iron–sulfur cluster","Biochemistry","Dithiol","Biology","Mutant","Glutathione","Sulfur metabolism","Cell biology","Chemistry","Enzyme","Gene","Iron-Sulfur Proteins","Models, Molecular","Forum Original Research Communications","Mice, Inbred BALB C","Molecular Sequence Data","Coenzymes","Protozoan Proteins","Parasitemia","Protein Structure, Secondary","Mitochondria","Mice","Catalytic Domain","Consensus Sequence","Animals","Female","Amino Acid Sequence","Cysteine","Nuclear Magnetic Resonance, Biomolecular","Glutaredoxins","Protein Binding"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. Good health"},{"sdg_number":0,"sdg_label":"Industry, innovation and infrastructure"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"pdb"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-17T14:15:57.069897Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}