Human glutaredoxin 3 can bind and effectively transfer [4Fe–4S] cluster to apo-iron regulatory protein 1

Xia, Haiyan; Li, Binghua; Zhang, Zhou; Wang, Qi; Qiao, Tong; Li, Kuanyu

doi:10.1016/j.bbrc.2015.08.073

Cited by 14 publications

(17 citation statements)

References 24 publications

(27 reference statements)

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“…The human MMS19 has been shown to be necessary for the maturation of only certain Fe-S proteins, mostly involved in DNA metabolism, but not for the activity of cytosolic aconitase iron regulated protein1 (IRP1) or Gln phosphoribosylpyrophosphate amidotransferase (Stehling et al, 2012). Human GRX3 is able to bind, in addition to [2Fe-2S] clusters, [4Fe-4S] clusters in vitro, which is necessary for the maturation of apo-IRP1 into aconitase (Xia et al, 2015), thus suggesting that GRX3/GRXS17, and not MMS19/MET18, is involved in the transfer of [4Fe-4S] clusters necessary for IRP1 maturation. This hypothesis is in accordance with the decrease in cytosolic aconitase activity observed in the Arabidopsis grxs17-1 mutant (Knuesting et al, 2015).…”

Section: Profiling Of Loss-of-function Grxs17 Plants Points To An Elementioning

confidence: 99%

Glutaredoxin GRXS17 Associates with the Cytosolic Iron-Sulfur Cluster Assembly Pathway

et al. 2016

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Cytosolic monothiol glutaredoxins (GRXs) are required in iron-sulfur (Fe-S) cluster delivery and iron sensing in yeast and mammals. In plants, it is unclear whether they have similar functions. Arabidopsis (Arabidopsis thaliana) has a sole class II cytosolic monothiol GRX encoded by GRXS17. Here, we used tandem affinity purification to establish that Arabidopsis GRXS17 associates with most known cytosolic Fe-S assembly (CIA) components. Similar to mutant plants with defective CIA components, grxs17 loss-of-function mutants showed some degree of hypersensitivity to DNA damage and elevated expression of DNA damage marker genes. We also found that several putative Fe-S client proteins directly bind to GRXS17, such as XANTHINE DEHYDROGENASE1 (XDH1), involved in the purine salvage pathway, and CYTOSOLIC THIOURIDYLASE SUBUNIT1 and CYTOSOLIC THIOURIDYLASE SUBUNIT2, both essential for the 2-thiolation step of 5-methoxycarbonylmethyl-2-thiouridine (mcm 5 s 2 U) modification of tRNAs. Correspondingly, profiling of the grxs17-1 mutant pointed to a perturbed flux through the purine degradation pathway and revealed that it phenocopied mutants in the elongator subunit ELO3, essential for the mcm 5 tRNA modification step, although we did not find XDH1 activity or tRNA thiolation to be markedly reduced in the grxs17-1 mutant. Taken together, our data suggest that plant cytosolic monothiol GRXs associate with the CIA complex, as in other eukaryotes, and contribute to, but are not essential for, the correct functioning of client Fe-S proteins in unchallenged conditions.

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Section: Profiling Of Loss-of-function Grxs17 Plants Points To An Elementioning

confidence: 99%

Glutaredoxin GRXS17 Associates with the Cytosolic Iron-Sulfur Cluster Assembly Pathway

et al. 2016

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“…1, 2 Studies in yeast and mammalian cells demonstrate that these Grx3/4 orthologs are critical for iron trafficking and signaling iron availability to iron regulatory proteins. 9–13 …”

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confidence: 99%

The Escherichia coli BolA Protein IbaG Forms a Histidine-Ligated [2Fe-2S]-Bridged Complex with Grx4

Dlouhy

Albetel

et al. 2016

Biochemistry

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Two ubiquitous protein families have emerged as key players in iron metabolism, the CGFS type monothiol glutaredoxins (Grxs) and the BolA proteins. Monothiol Grxs and BolA proteins form heterocomplexes that have been implicated in Fe-S cluster assembly and trafficking. The E. coli genome encodes members of both of these proteins families, namely the monothiol glutaredoxin Grx4, and two BolA family proteins, BolA and IbaG. Previous work has demonstrated that E. coli Grx4 and BolA interact as both apo and [2Fe-2S]-bridged heterodimers that are spectroscopically distinct from [2Fe-2S]-bridged Grx4 homodimers. However, the physical and functional interactions between Grx4 and IbaG are uncharacterized. Here we show that co-expression of Grx4 with IbaG yields a [2Fe-2S]-bridged Grx4-IbaG heterodimer. In vitro interaction studies indicate that IbaG binds the [2Fe-2S] Grx4 homodimer to form apo Grx4-IbaG heterodimers as well as the [2Fe-2S] Grx4-IbaG heterodimer, altering the cluster stability and coordination environment. Additionally, spectroscopic and mutagenesis studies provide evidence that IbaG ligates the Fe-S cluster via the conserved histidine that is present in all BolA proteins and by a second conserved histidine that is present in the H/C loop of two of the four classes of BolA proteins. These results suggest that IbaG may function in Fe-S cluster assembly and trafficking in E. coli as demonstrated for other BolA homologues that interact with monothiol Grxs.

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“…However, the protein functional aspects are conserved, with formation of a heterodimeric BolA‐Grx3 complex that can bind and deliver a [2Fe‐2S] cluster to the cytosolic assembly protein Ciapin1 (Dre2 homolog) to initiate downstream cluster transfer in the cytosol . Moreover, human Grx3 has the potential to regulate iron homeostasis via delivery of a cluster to the iron regulatory protein, IRP .…”

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Cytosolic iron–sulfur cluster transfer—a proposed kinetic pathway for reconstitution of glutaredoxin 3

2016

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Iron-sulfur clusters are ubiquitously conserved and play essential cellular roles. The mechanism of Fe-S cluster biogenesis involves multiple proteins in a complex pathway. Cluster biosynthesis primarily occurs in the mitochondria, but key Fe-S proteins also exist in the cytosol. One such protein, glutaredoxin 3 (Grx3), is involved in iron regulation, sensing and mediating [2Fe-2S] cluster delivery to cytosolic protein targets, but the cluster donor for cytosolic Grx3 has not been elucidated. Herein, we delineate the kinetic transfer of [2Fe-2S] clusters into Grx3 from potential cytosolic carrier/scaffold proteins, IscU and Nfu, to evaluate a possible model for Grx3 reconstitution in vivo.

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Human glutaredoxin 3 can bind and effectively transfer [4Fe–4S] cluster to apo-iron regulatory protein 1

Cited by 14 publications

References 24 publications

Glutaredoxin GRXS17 Associates with the Cytosolic Iron-Sulfur Cluster Assembly Pathway

Glutaredoxin GRXS17 Associates with the Cytosolic Iron-Sulfur Cluster Assembly Pathway

The Escherichia coli BolA Protein IbaG Forms a Histidine-Ligated [2Fe-2S]-Bridged Complex with Grx4

Cytosolic iron–sulfur cluster transfer—a proposed kinetic pathway for reconstitution of glutaredoxin 3

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