Characterization of the human monothiol glutaredoxin 3 (PICOT) as iron–sulfur protein

Haunhorst, Petra; Berndt, Carsten; Eitner, Susanne; Godoy, José R.; Lillig, Christopher Horst

doi:10.1016/j.bbrc.2010.03.016

Cited by 91 publications

(114 citation statements)

References 23 publications

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“…A recent structural analysis of the TXNL2 yeast homolog confirmed that the cysteine in Grx domain may have catalytic activity (68). This is also supported by a recent study, indicating that TXNL2 binds 2 bridging [2Fe-2S] clusters in a homodimeric complex with the active site Cys residues of its 2 Grx domains and GSH bound non-covalently to the Grx domains (69).…”

Section: Txnl2 Is a Key Component In Regulating Intracellular Ros Levsupporting

confidence: 59%

Thioredoxin-like 2 regulates human cancer cell growth and metastasis via redox homeostasis and NF-κB signaling

et al. 2011

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Cancer cells have an efficient antioxidant system to counteract their increased generation of ROS. However, whether this ability to survive high levels of ROS has an important role in the growth and metastasis of tumors is not well understood. Here, we demonstrate that the redox protein thioredoxin-like 2 (TXNL2) regulates the growth and metastasis of human breast cancer cells through a redox signaling mechanism. TXNL2 was found to be overexpressed in human cancers, including breast cancers. Knockdown of TXNL2 in human breast cancer cell lines increased ROS levels and reduced NF-κB activity, resulting in inhibition of in vitro proliferation, survival, and invasion. In addition, TXNL2 knockdown inhibited tumorigenesis and metastasis of these cells upon transplantation into immunodeficient mice. Furthermore, analysis of primary breast cancer samples demonstrated that enhanced TXNL2 expression correlated with metastasis to the lung and brain and with decreased overall patient survival. Our studies provided insight into redox-based mechanisms underlying tumor growth and metastasis and suggest that TXNL2 could be a target for treatment of breast cancer.

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Section: Txnl2 Is a Key Component In Regulating Intracellular Ros Levsupporting

confidence: 59%

Thioredoxin-like 2 regulates human cancer cell growth and metastasis via redox homeostasis and NF-κB signaling

et al. 2011

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“…Each of the monothiol glutaredoxin domains contains an active site with the conserved CGFS motif. Both human and yeast Grx3 can form homodimers containing a bridging 2Fe-2S cluster that is coordinated through the active site cysteines and two molecules of glutathione (34,35). In vitro, the Fe-S cluster bound by the Grx3 homodimer is labile and lost in the presence of oxygen or reductant.…”

Section: Monothiol Glutaredoxinsmentioning

confidence: 99%

Coming into View: Eukaryotic Iron Chaperones and Intracellular Iron Delivery

Philpott

2012

Journal of Biological Chemistry

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Eukaryotic cells contain hundreds of metalloproteins, and ensuring that each protein receives the correct metal ion is a critical task for cells. Recent work in budding yeast and mammalian cells has uncovered a system of iron delivery operating in the cytosolic compartment that involves monothiol glutaredoxins, which bind iron in the form of iron-sulfur clusters, and poly(rC)-binding proteins, which bind Fe(II) directly. In yeast cells, cytosolic monothiol glutaredoxins are required for the formation of heme and iron-sulfur clusters and the metallation of some non-heme iron enzymes. Poly(rC)-binding proteins can act as iron chaperones, delivering iron to target non-heme enzymes through direct protein-protein interactions. Although the molecular details have yet to be explored, these proteins, acting independently or together, may represent the basic cellular machinery for intracellular iron delivery.Metalloproteins are very abundant in all types of cells, where they perform a plethora of enzymatic and regulatory functions. A variety of transition metal ions contribute to the metalloproteome of a cell, with iron and zinc being the most abundant (1). Estimates of the number of cellular proteins containing metal ions vary substantially, and evidence from bacteria suggests that many of the proteins that contain metal ions have not yet been annotated as metalloproteins (2). One method of estimating the prevalence of metalloproteins is to examine structural databases. A survey of enzymes for which three-dimensional structures have been determined indicated that 9% contained zinc, 8% iron, 6% manganese (in many cases, the biologically relevant metal is magnesium), and 1% copper (3). A second approach involves the identification of metalloproteins based on the homology of metal-binding domains and metal-binding sites of known metalloproteins to protein sequences derived from sequenced genomes. This type of bioinformatics approach indicates that zinc proteins constitute ϳ10% of the eukaryotic proteome, non-heme iron proteins account for ϳ1% of the proteome, and copper proteins are Ͻ1% of the proteome (4).Given the presence of so many different metalloproteins, the cell faces several obstacles in ensuring that apoproteins receive the correct metal ion. First, although the primary coordination spheres of metal-binding sites can readily exclude ions based on charge, coordination geometry, and polarity, these sites may not have the capacity to discriminate between divalent metal cations and may even bind a non-cognate metal more tightly than the correct one (1). Second, some metal ions, such as iron and copper, are redox-active and, in the presence of oxygen, can catalyze the formation of dangerous reactive oxygen species. Thus, cells must tightly regulate the uptake and distribution of these metals to use them while avoiding the twin toxicities of mismetallation and oxidative damage. One cellular strategy is to maintain the pools of "free" or unliganded metals at exceedingly low levels. This appears to be especially true fo...

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“…The yeast GRX proteins Grx3/4 and the mammalian ortholog GRX3/PKC-interacting cousin of TRX (PICOT) have been associated with the CIA pathway and contain themselves [2Fe-2S] clusters (Picciocchi et al, 2007;Haunhorst et al, 2010). Deletion of Grx3/4 in yeast leads to defects in cytosolic and mitochondrial Fe-S assembly, deregulation of iron homeostasis, and defects in proteins containing di-iron centers (Mühlenhoff et al, 2010).…”

mentioning

confidence: 99%

“…Deletion of Grx3/4 in yeast leads to defects in cytosolic and mitochondrial Fe-S assembly, deregulation of iron homeostasis, and defects in proteins containing di-iron centers (Mühlenhoff et al, 2010). Yeast Grx3/4 and human GRX3 belong to the PICOT protein family and contain one N-terminal TRX and one (Grx3/4) or two (GRX3) C-terminal GRX domains, also known as PICOT homology domains (Haunhorst et al, 2010). Because they contain only a single Cys residue in their GRX active sites, they are classified as monothiol GRXs.…”

mentioning

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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Characterization of the human monothiol glutaredoxin 3 (PICOT) as iron–sulfur protein

Cited by 91 publications

References 23 publications

Thioredoxin-like 2 regulates human cancer cell growth and metastasis via redox homeostasis and NF-κB signaling

Thioredoxin-like 2 regulates human cancer cell growth and metastasis via redox homeostasis and NF-κB signaling

Coming into View: Eukaryotic Iron Chaperones and Intracellular Iron Delivery

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

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