PMID- 30209332
OWN - NLM
STAT- MEDLINE
DCOM- 20191031
LR  - 20191031
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 8
IP  - 1
DP  - 2018 Sep 12
TI  - The lineage-specific, intrinsically disordered N-terminal extension of monothiol 
      glutaredoxin 1 from trypanosomes contains a regulatory region.
PG  - 13716
LID - 10.1038/s41598-018-31817-4 [doi]
LID - 13716
AB  - 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.
FAU - Sturlese, Mattia
AU  - Sturlese M
AUID- ORCID: 0000-0003-3944-0313
AD  - Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131, 
      Padova, Italy.
AD  - Molecular Modeling Section (MMS), Department of Pharmaceutical and 
      Pharmacological Sciences, University of Padova, via Marzolo 5, Padova, Italy.
FAU - Manta, Bruno
AU  - Manta B
AUID- ORCID: 0000-0001-8366-8935
AD  - Institut Pasteur de Montevideo, Mataojo 2020, 11400, Montevideo, Uruguay.
AD  - Laboratorio de Fisicoquimica Biologica, Instituto de Quimica Biologica, Facultad 
      de Ciencias, Universidad de la Republica, Igua 4425, 11400, Montevideo, Uruguay.
AD  - New England Biolabs, 240 County Road, Ipswich, MA, 01938, USA.
FAU - Bertarello, Andrea
AU  - Bertarello A
AD  - Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131, 
      Padova, Italy.
FAU - Bonilla, Mariana
AU  - Bonilla M
AD  - Institut Pasteur de Montevideo, Mataojo 2020, 11400, Montevideo, Uruguay.
FAU - Lelli, Moreno
AU  - Lelli M
AUID- ORCID: 0000-0002-7042-2335
AD  - Department of Chemistry "Ugo Schiff", University of Florence, Via della 
      Lastruccia 3, 50019, Sesto Fiorentino (FI), Italy.
AD  - Magnetic Resonance Center (CERM), University of Florence, Via L. Sacconi 6, 
      50019, Sesto Fiorentino (FI), Italy.
AD  - Centre de RMN a Tres Hauts Champs, Institut des Sciences Analytiques (UMR 5280 - 
      CNRS, ENS Lyon, UCB Lyon 1), Universite de Lyon, 5 rue de la Doua, 69100, 
      Villeurbanne, France.
FAU - Zambelli, Barbara
AU  - Zambelli B
AUID- ORCID: 0000-0002-3876-0051
AD  - Department of Pharmacy and Biotechnology, University of Bologna, Viale Giuseppe 
      Fanin 40, 40127, Bologna, Italy.
FAU - Grunberg, Karin
AU  - Grunberg K
AD  - Institut Pasteur de Montevideo, Mataojo 2020, 11400, Montevideo, Uruguay.
FAU - Mammi, Stefano
AU  - Mammi S
AD  - Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131, 
      Padova, Italy.
FAU - Comini, Marcelo A
AU  - Comini MA
AUID- ORCID: 0000-0001-5000-1333
AD  - Institut Pasteur de Montevideo, Mataojo 2020, 11400, Montevideo, Uruguay.
FAU - Bellanda, Massimo
AU  - Bellanda M
AUID- ORCID: 0000-0002-8187-0264
AD  - Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131, 
      Padova, Italy. massimo.bellanda@unipd.it.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180912
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Glutaredoxins)
RN  - 0 (Iron-Sulfur Proteins)
RN  - 70FD1KFU70 (Sulfur)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Amino Acid Sequence
MH  - Catalytic Domain/physiology
MH  - Glutaredoxins/metabolism
MH  - Glutathione/metabolism
MH  - Iron-Sulfur Proteins/*metabolism
MH  - Oxidation-Reduction
MH  - Protein Conformation
MH  - Protein Multimerization/physiology
MH  - Regulatory Sequences, Nucleic Acid/*physiology
MH  - Sulfur/*metabolism
MH  - Trypanosoma/*metabolism
MH  - Trypanosoma brucei brucei/*metabolism
PMC - PMC6135854
COIS- The authors declare no competing interests.
EDAT- 2018/09/14 06:00
MHDA- 2019/11/02 06:00
PMCR- 2018/09/12
CRDT- 2018/09/14 06:00
PHST- 2018/04/16 00:00 [received]
PHST- 2018/08/23 00:00 [accepted]
PHST- 2018/09/14 06:00 [entrez]
PHST- 2018/09/14 06:00 [pubmed]
PHST- 2019/11/02 06:00 [medline]
PHST- 2018/09/12 00:00 [pmc-release]
AID - 10.1038/s41598-018-31817-4 [pii]
AID - 31817 [pii]
AID - 10.1038/s41598-018-31817-4 [doi]
PST - epublish
SO  - Sci Rep. 2018 Sep 12;8(1):13716. doi: 10.1038/s41598-018-31817-4.