Cluster exchange reactivity of [2Fe‐2S]‐bridged heterodimeric BOLA1‐GLRX5

Sen, Sambuddha; Hendricks, Amber L.; Cowan, J. A.

doi:10.1111/febs.15452

Cited by 6 publications

(3 citation statements)

References 33 publications

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“…Two BolA3-Grx5 hetero-complexes can transfer their Fe 2 S 2 clusters to Nfu1 to form a Fe 4 S 4 cluster in FeS protein maturation [ 126 ]. A role in cluster trafficking was ruled out for BolA1-Grx5 because of its structurally buried cluster and the lack of transfer efficiency to common Fe 2 S 2 cluster acceptors, such as ferredoxins [ 123 ]. Patients with mutations in the Grx5 or the BolA3 gene suffer from variations of nonketotic hyperglycinemia with decreased lipoylation, likely caused by interruption of the cluster transfer pathway to the FeS protein lipoate synthase [ 110 ].…”

Section: Glutathione Glutaredoxins and Iron-metabolismmentioning

confidence: 99%

Role of GSH and Iron-Sulfur Glutaredoxins in Iron Metabolism—Review

et al. 2020

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Glutathione (GSH) was initially identified and characterized for its redox properties and later for its contributions to detoxification reactions. Over the past decade, however, the essential contributions of glutathione to cellular iron metabolism have come more and more into focus. GSH is indispensable in mitochondrial iron-sulfur (FeS) cluster biosynthesis, primarily by co-ligating FeS clusters as a cofactor of the CGFS-type (class II) glutaredoxins (Grxs). GSH is required for the export of the yet to be defined FeS precursor from the mitochondria to the cytosol. In the cytosol, it is an essential cofactor, again of the multi-domain CGFS-type Grxs, master players in cellular iron and FeS trafficking. In this review, we summarize the recent advances and progress in this field. The most urgent open questions are discussed, such as the role of GSH in the export of FeS precursors from mitochondria, the physiological roles of the CGFS-type Grx interactions with BolA-like proteins and the cluster transfer between Grxs and recipient proteins.

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Section: Glutathione Glutaredoxins and Iron-metabolismmentioning

confidence: 99%

Role of GSH and Iron-Sulfur Glutaredoxins in Iron Metabolism—Review

et al. 2020

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“…The cluster release protein complex that extracts the cluster from ISCU is formed by HSPA9 (a HSP70 protein), HSC20 (a DnaJ chaperon protein that acts facilitating the transferring from ISCU to Grx5), GRPE1 (the nucleotide exchange factor that cycles ATP on Ssq1 for cluster transfer), and Grx5 (a glutaredoxin that interacts with HSPA9 and transfers [2Fe-2S] clusters to target proteins) [ 28 ]. Even though it was previously suggested that BOLA1 might assist Grx5 in cluster delivery, new experimental evidence discarded the direct role for the heterodimer Grx5-[2Fe-2S]-BOLA1 in cluster trafficking at least in humans [ 29 ]. On the other hand, Nasta and coworkers showed that the human Grx5-BOLA3 complex can transfers [2Fe-2S] 2+ cluster to the apo form of NFU1 yielding, in the presence of a reductant, a (4Fe-4S) 2+ cluster [ 30 ], whereas NFU1 may transfer the latter complex to client proteins like aconitase [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

A Highly Conserved Iron-Sulfur Cluster Assembly Machinery between Humans and Amoeba Dictyostelium discoideum: The Characterization of Frataxin

Olmos

Pignataro

Santos

et al. 2020

IJMS

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Several biological activities depend on iron–sulfur clusters ([Fe-S]). Even though they are well-known in several organisms their function and metabolic pathway were poorly understood in the majority of the organisms. We propose to use the amoeba Dictyostelium discoideum, as a biological model to study the biosynthesis of [Fe-S] at the molecular, cellular and organism levels. First, we have explored the D. discoideum genome looking for genes corresponding to the subunits that constitute the molecular machinery for Fe-S cluster assembly and, based on the structure of the mammalian supercomplex and amino acid conservation profiles, we inferred the full functionality of the amoeba machinery. After that, we expressed the recombinant mature form of D. discoideum frataxin protein (DdFXN), the kinetic activator of this pathway. We characterized the protein and its conformational stability. DdFXN is monomeric and compact. The analysis of the secondary structure content, calculated using the far-UV CD spectra, was compatible with the data expected for the FXN fold, and near-UV CD spectra were compatible with the data corresponding to a folded protein. In addition, Tryptophan fluorescence indicated that the emission occurs from an apolar environment. However, the conformation of DdFXN is significantly less stable than that of the human FXN, (4.0 vs. 9.0 kcal mol−1, respectively). Based on a sequence analysis and structural models of DdFXN, we investigated key residues involved in the interaction of DdFXN with the supercomplex and the effect of point mutations on the energetics of the DdFXN tertiary structure. More than 10 residues involved in Friedreich’s Ataxia are conserved between the human and DdFXN forms, and a good correlation between mutational effect on the energetics of both proteins were found, suggesting the existence of similar sequence/function/stability relationships. Finally, we integrated this information in an evolutionary context which highlights particular variation patterns between amoeba and humans that may reflect a functional importance of specific protein positions. Moreover, the complete pathway obtained forms a piece of evidence in favor of the hypothesis of a shared and highly conserved [Fe-S] assembly machinery between Human and D. discoideum.

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“…11 Among the possible Fe 2+ mitochondrial chelators, the most quoted, because of its very high concentration in the mitochondrial matrix, given in the range of 10–14 mM, is glutathione (GSH). 12 It was proposed that a Fe 2+ -glutathione adduct ([Fe II (H 2 O) 5 GS] + ) is the major non-proteinacious LMM Fe complex in the mitochondrial matrix and that a glutathione-coordinated [Fe 2 S 2 (GS) 4 ] 2− complex might be also part of the mitochondrial LIP 10,11 a to be used as reservoir for the mitochondrial [Fe–S] cluster assembly machinery 13 as well as to be transferred to the cytosol. 5 However, the exact composition of the non-proteinacious LMM complexes detected in mitochondria still needs to be addressed.…”

mentioning

confidence: 99%