title: A New Class of Thioredoxin-Related Protein Able to Bind Iron-Sulfur Clusters.
abstract: Members of the thioredoxin (Trx) protein family participate mainly in redox pathways and have not been associated with Fe/S binding, in contrast to some closely related glutaredoxins (Grxs). Cestode parasites possess an unusual diversity of Trxs and Trx-related proteins with unexplored functions. In this study, we addressed the biochemical characterization of a new class of Trx-related protein (IsTRP) and a classical monothiol Grx (EgGrx5) from the human pathogen Echinococcus granulosus.
  
  
  
  The dimeric form of IsTRP coordinates Fe2S2in a glutathione-independent manner; instead, Fe/S binding relies on the CXXC motif conserved among Trxs. This novel binding mechanism allows holo-IsTRP to be highly resistant to oxidation. IsTRP lacks canonical reductase activities. Mitochondrially targeted IsTRP aids growth of a Grx5 null yeast strain. Similar complementation assays performed with EgGrx5 revealed functional conservation for class II Grxs, despite the presence of nonconserved structural elements. IsTRP is a cestode lineage-specific protein highly expressed in the gravid adult worm, which releases the infective stage critical for dissemination.
  
  
  
  IsTRP is the first member from the Trx family to be reported to bind Fe/S. We disclose a novel mechanism of Fe/S coordination within the Trx folding unit, which renders the cluster highly resistant to oxidation-mediated disassembly.
  
  
  
  We demonstrate that IsTRP defines a new protein family within the Trx superfamily, confirm the conservation of function for class II Grx from nonphylogenetically related species, and highlight the versatility of the Trx folding unit to acquire Fe/S binding as a recurrent emergent function. Antioxid. Redox Signal. 00, 000-000.
authors.affiliation: 1 Worm Biology Laboratory, Institut Pasteur de Montevideo, Montevideo, Uruguay .
authors.forename: Hugo
authors.initials: H
authors.lastname: Bisio
authors.affiliation: 2 Redox Biology of Trypanosomes Laboratory, Institut Pasteur de Montevideo , Montevideo, Uruguay .
authors.forename: Mariana
authors.initials: M
authors.lastname: Bonilla
authors.affiliation: 2 Redox Biology of Trypanosomes Laboratory, Institut Pasteur de Montevideo , Montevideo, Uruguay .
authors.forename: Bruno
authors.initials: B
authors.lastname: Manta
authors.affiliation: 3 Bioinformatics Unit, Institut Pasteur de Montevideo , Montevideo, Uruguay .
authors.forename: Martín
authors.initials: M
authors.lastname: Graña
authors.affiliation: 4 Cellular Membranes Laboratory, Institut Pasteur de Montevideo , Montevideo, Uruguay .
authors.forename: Valentina
authors.initials: V
authors.lastname: Salzman
authors.affiliation: 4 Cellular Membranes Laboratory, Institut Pasteur de Montevideo , Montevideo, Uruguay .
authors.forename: Pablo S
authors.initials: PS
authors.lastname: Aguilar
authors.affiliation: 5 Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston, Massachusetts.
authors.forename: Vadim N
authors.initials: VN
authors.lastname: Gladyshev
authors.affiliation: 2 Redox Biology of Trypanosomes Laboratory, Institut Pasteur de Montevideo , Montevideo, Uruguay .
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Comini
authors.affiliation: 1 Worm Biology Laboratory, Institut Pasteur de Montevideo, Montevideo, Uruguay .|6 Cátedra de Inmunología, Departamento de Biociencias, Facultad de Química, Universidad de la República , Montevideo, Uruguay .
authors.forename: Gustavo
authors.initials: G
authors.lastname: Salinas