The roles of glutaredoxins ligating Fe–S clusters: Sensing, transfer or repair functions?

Abstract

Glutaredoxins (Grxs) are major oxidoreductases involved in the reduction of glutathionylated proteins. Owing to the capacity of several class I Grxs and likely all class II Grxs to incorporate iron-sulfur (Fe-S) clusters, they are also linked to iron metabolism. Most Grxs bind [2Fe-2S] clusters which are oxidatively- and reductively-labile and have identical ligation, involving notably external glutathione. However, subtle differences in the structural organization explain that class II Fe-S Grxs, having more labile and solvent-exposed clusters, can accept Fe-S clusters and transfer them to client proteins, whereas class I Fe-S Grxs usually do not. From the observed glutathione disulfide-mediated Fe-S cluster degradation, the current view is that the more stable Fe-S clusters found in class I Fe-S Grxs might constitute a sensor of oxidative stress conditions by modulating their activity. Indeed, in response to an oxidative signal, inactive holoforms i.e., without disulfide reductase activity, should be converted to active apoforms. Among class II Fe-S Grxs, monodomain Grxs likely serve as carrier proteins for the delivery of preassembled Fe-S clusters to acceptor proteins in organelles. Another proposed function is the repair of Fe-S clusters. From their cytoplasmic and/or nuclear localization, multidomain Grxs function in signalling pathways. In particular, they regulate iron homeostasis in yeast species by modulating the activity of transcription factors and eventually forming heterocomplexes with BolA-like proteins in response to the cellular iron status. We provide an overview of the biochemical and structural properties of Fe-S cluster-loaded Grxs in relation to their hypothetical or confirmed associated functions. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases.

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

“…Arabidopsis GRXS17 loss-of-function plants (grxs17) are hypersensitive to heat stress and show alterations in auxin sensitivity and polar transport (Cheng et al, 2011). The molecular function of an association of cytosolic monothiol GRX with Fe-S clusters and the CIA pathway has been a subject of debate, and a role in Fe, Fe-S, or oxidative signaling has been proposed, in addition to a role in delivery or repair of Fe-S clusters (Couturier et al, 2015). Recently, delivery of an Fe-S cluster by human GRX3 to the CIA pathway component DRE2/Anamorsin has been demonstrated (Banci et al, 2015).…”

Roles and maturation of iron–sulfur proteins in plastids

“…Two subgroups can, however, be distinguished based on the length of the β1–β2 loop referred to as the variable [C/H] loop, because it contains one of the ligands provided by BOLA either a cysteine or a histidine, the second ligand being a totally conserved histidine found in the α3–β3 loop [39, 48]. Other cysteine ligands are provided by a glutathione molecule and by the one present in the conserved CGFS signature of the GRX partner, as in regular GRX homodimers [51]. While there is no true ortholog of yeast Bol3 in plants, the observation that Bol3 might interact with Nfu1 rather than with Grx5 in yeast could point to a different role in the late steps of the mitochondrial system [47, 48].…”

Plant-specific CC-type glutaredoxins: functions in developmental processes and stress responses

“…Whereas wildtype Arabidopsis flowers form 4.0 equally shaped petals, roxy1 mutants initiate on average only 2.5 petal primordia and later petal morphogenesis is often disturbed ( Figure 3). Surprisingly, cloning of the affected gene revealed loss-of-function of a GRX, which, after confirmation by analysis of two additional independent T-DNA mutant lines, was named ROXY1 (Xing et al, 2005) far, GRXs were known to participate as oxidoreductases in fundamental processes such as reduction of nucleotides for DNA synthesis and in responses to oxidative stress (Lillig et al, 2008;Rouhier et al, 2008;Couturier et al, 2009aCouturier et al, , 2014Lillig and Berndt, 2013). The following analyses of ROXYs and their homologs in Arabidopsis and other species, such as maize and rice, further supported their importance in governing different floral processes, which are summarized below.…”

“…The last glutathione anchor point is formed by the interaction of the γ-glutamyl group of glutathione with a polar aspartate group following a characteristic GG motif. This binding mode is not only utilized during the catalytic cycle, but some GRXs accommodate non-covalently bound glutathione within the same binding area in order to coordinate a [2Fe-2S] cluster (Couturier et al, 2014). Figure 8C depicts an alignment of the critical amino acids of all Arabidopsis GRXs.…”

“…Furthermore, members of both classes of GRXs form complexes with iron-sulfur [2Fe-2S] clusters along with glutathione (Muhlenhoff et al, 2003;Bandyopadhyay et al, 2008;Haunhorst et al, 2010;Couturier et al, 2014). For class I GRX hGRX2, it has been suggested that dissociation of the complex under limiting levels of reduced glutathione could serve to control the oxidoreductase activity of the protein (Lillig et al, 2005).…”