Mechanism of frataxin “bypass” in human iron–sulfur cluster biosynthesis with implications for Friedreich's ataxia

  title={Mechanism of frataxin “bypass” in human iron–sulfur cluster biosynthesis with implications for Friedreich's ataxia},
  author={Deepika Das and Shachin Patra and Jennifer Bridwell-Rabb and David P. Barondeau},
  journal={The Journal of Biological Chemistry},
  pages={9276 - 9284}
In humans, mitochondrial iron–sulfur cluster biosynthesis is an essential biochemical process mediated by the assembly complex consisting of cysteine desulfurase (NFS1), LYR protein (ISD11), acyl-carrier protein (ACP), and the iron–sulfur cluster assembly scaffold protein (ISCU2). The protein frataxin (FXN) is an allosteric activator that binds the assembly complex and stimulates the cysteine desulfurase and iron–sulfur cluster assembly activities. FXN depletion causes loss of activity of iron… Expand
8 Citations
Mechanism of activation of the human cysteine desulfurase complex by frataxin
It is shown that FXN accelerates Fe-S cluster formation by positioning a mobile loop cysteine of the assembly complex to interact with the substrate and function as an acid, nucleophile, and sulfur carrier during the reaction. Expand
Recapitulating the frataxin activation mechanism in an engineered bacterial cysteine desulfurase supports the architectural switch model
Overall, studies indicate a weakening of the homodimeric interface was a key development during the evolution of the eukaryotic system and provide new insights into the role of FXN. Expand
Role of GSH and Iron-Sulfur Glutaredoxins in Iron Metabolism—Review
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. Expand
Making iron-sulfur cluster: structure, regulation and evolution of the bacterial ISC system.
This review aims to highlight Fe-S biogenesis facets remaining matters of discussion, such as the role of frataxin, or the link between fatty acid metabolism andFe-S homeostasis, and discusses recent advances on strategies used by different species to make and use Fe- S clusters in changing redox environmental conditions. Expand
Down the Iron Path: Mitochondrial Iron Homeostasis and Beyond
This work focuses on describing the processes of and components involved in mitochondrial iron trafficking and storage, as well as mitochondrial iron–sulfur cluster biogenesis and heme biosynthesis. Expand
From Rust to Quantum Biology: The Role of Iron in Retina Physiopathology
Evidence is summarized of the potential therapeutic effect of iron chelation in retinal diseases and especially the interest of transferrin, a ubiquitous endogenous iron-binding protein, having the ability to treat or delay degenerative Retinal diseases. Expand
Mitochondrial dysfunction in neurons in Friedreich's ataxia
Current knowledge on frataxin expression in different tissues is reviewed, the molecular function of fratAXin is discussed, and the consequences of its deficiency for mitochondria structural and functional properties are discussed, with a focus on the nervous system. Expand
A severe form of autosomal recessive spinocerebellar ataxia associated with novel PMPCA variants
A case of a 15-year-old Japanese girl with infancy-onset, very severe and progressive developmental delay, cerebellar ataxia, and extrapyramidal symptoms, diagnosed as SCAR2, which might provide a new insight into PMPCA gene-related disorders and expand the disease concept. Expand


Human Frataxin Activates Fe–S Cluster Biosynthesis by Facilitating Sulfur Transfer Chemistry
Radiolabeling experiments indicate FXN accelerates the accumulation of sulfur on ISCU2 and that the resulting persulfide species is viable in the subsequent synthesis of Fe–S clusters, which cannot be fully explained by the hypothesis that FXN functions as an iron donor for Fe-S cluster biosynthesis. Expand
Mammalian frataxin controls sulfur production and iron entry during de novo Fe4S4 cluster assembly.
It is shown that FXN stabilizes the quaternary complex and controls iron entry to the complex through activation of cysteine desulfurization, and in the presence of iron and L-cysteine, an [Fe(4)S(4)] cluster is formed within the quaternal complex that can be transferred to mammalian aconitase (mACO2) to generate an active enzyme. Expand
Human frataxin is an allosteric switch that activates the Fe-S cluster biosynthetic complex.
In vitro evidence is provided that human frataxin binds to a Nfs1, Isd11, and Isu2 complex to generate the four-component core machinery for Fe-S cluster biosynthesis, and a model in which cellular fr ataxin levels regulate human Fe- S cluster biosynthetic activities is proposed that has implications for mitochondrial dysfunction, oxidative stress response, and both neurodegenerative and cardiovascular disease. Expand
Human ISD11 is essential for both iron-sulfur cluster assembly and maintenance of normal cellular iron homeostasis.
It is shown that human ISD11 forms a stable complex in vivo with the human cysteine desulfurase (ISCS), which generates the inorganic sulfur needed for Fe-S protein biogenesis. Expand
Mutation in the Fe-S scaffold protein Isu bypasses frataxin deletion.
It is reported that a single amino acid substitution (methionine to isoleucine) at position 107 in the mature form of Isu1 restored many deficient functions in Δyfh1 or frataxin-depleted yeast cells and iron homoeostasis was improved such that soluble/usable mitochondrial iron was increased and accumulation of insoluble/non-usable iron within mitochondria was largely prevented. Expand
Monomeric yeast frataxin is an iron-binding protein.
The binding properties and metal-site structure of ferrous iron bound to monomeric yeast frataxin are characterized and a model for how the protein can bind two ferrous Iron atoms with micromolar binding affinity is developed. Expand
Iron-sulfur protein maturation in human cells: evidence for a function of frataxin.
It is demonstrated that frataxin is a component of the human Fe/S cluster assembly machinery and that it plays a role in the maturation of both mitochondrial and cytosolicFe/S proteins. Expand
Structure of human Fe–S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP–ISD11 interactions
The unexpected architecture for the SDA complex provides a framework for understanding interactions with acceptor proteins for sulfur-containing biosynthetic pathways, elucidating mechanistic details of eukaryotic Fe–sulfur cluster biosynthesis, and clarifying how defects in Fe–S cluster assembly lead to diseases such as Friedreich’s ataxia. Expand
Interaction of frataxin, an iron binding protein, with IscU of Fe-S clusters biogenesis pathway and its upregulation in AmpB resistant Leishmania donovani.
The results suggest the role of Ld-frataxin as an iron binding/carrier protein for Fe-S cluster biogenesis that physically interacts with other core components of the ISC machinery within the mitochondria. Expand
Frataxin Directly Stimulates Mitochondrial Cysteine Desulfurase by Exposing Substrate-binding Sites, and a Mutant Fe-S Cluster Scaffold Protein with Frataxin-bypassing Ability Acts Similarly*♦
Using purified proteins and isolated mitochondria, it is shown that the yeast frataxin homolog (Yfh1) directly and specifically stimulates cysteine binding to Nfs1 by exposing substrate-binding sites, explaining the bypassing activity. Expand