Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly

Cai, Kai; Frederick, Ronnie O.; Tonelli, Marco; Markley, John L.

doi:10.1016/j.jinorgbio.2018.03.007

Cited by 52 publications

(61 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…From MD data analysis it turns out that the only two mutants that have the same behavior as wild‐type FXN (with respect to the interaction with IscS) are p.Y123S and p.S181F. On the contrary, considering the SASA of the residues involved in the interaction with IscU (Cai et al, ) it turns out that Trp155 is less exposed to the solvent (has a smaller SASA value than the wild type) only in p.Y123S and p.S181F, thus possibly meaning that the two mutants have a weaker interaction than all the other mutants (and the wild type) with IscU.…”

Section: Resultsmentioning

confidence: 99%

“…Fe-S clusters are protein cofactors involved in several cellular processes from respiration to DNA replication and repair. The clusters are assembled in the presence of the pyridoxal dependent cysteine desulfurase (NFS1 in human), the iron delivery protein frataxin (FXN), reductant ferredoxin, and a scaffold protein (IscU) (Cai, Frederick, Tonelli, & Markley, 2018a). Decreased level of expression of the ironbinding protein human FXN involved in Fe-S cluster assembly is associated with Friedreich ataxia (FRDA; MIM# 229300), a neurodegenerative disease characterized by neuronal death, cardiomyopathy, and diabetes (Correia, Pastore, Adinolfi, Pastore, & Gomes, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…interaction with IscU (Cai et al, 2018a) it turns out that Trp155 is less exposed to the solvent (has a smaller SASA value than the wild type) only in p.Y123S and p.S181F, thus possibly meaning that the two mutants have a weaker interaction than all the other mutants (and the wild type) with IscU.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Characterization of human frataxin missense variants in cancer tissues

et al. 2019

View full text Add to dashboard Cite

Human frataxin is an iron‐binding protein involved in the mitochondrial iron–sulfur (Fe–S) clusters assembly, a process fundamental for the functional activity of mitochondrial proteins. Decreased level of frataxin expression is associated with the neurodegenerative disease Friedreich ataxia. Defective function of frataxin may cause defects in mitochondria, leading to increased tumorigenesis. Tumor‐initiating cells show higher iron uptake, a decrease in iron storage and a reduced Fe–S clusters synthesis and utilization. In this study, we selected, from COSMIC database, the somatic human frataxin missense variants found in cancer tissues p.D104G, p.A107V, p.F109L, p.Y123S, p.S161I, p.W173C, p.S181F, and p.S202F to analyze the effect of the single amino acid substitutions on frataxin structure, function, and stability. The spectral properties, the thermodynamic and the kinetic stability, as well as the molecular dynamics of the frataxin missense variants found in cancer tissues point to local changes confined to the environment of the mutated residues. The global fold of the variants is not altered by the amino acid substitutions; however, some of the variants show a decreased stability and a decreased functional activity in comparison with that of the wild‐type protein.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Characterization of human frataxin missense variants in cancer tissues

et al. 2019

View full text Add to dashboard Cite

show abstract

“…This explains why FXN alone cannot bind ISCU without NFS1. 10,12,20 FXN binds to two key regions on ISCU. One ISCU-FXN interface is through the conserved ISCU Ala-loop (Ala66-Asp71), contributing the conserved Cys69 that is required for ISC biosynthesis and interacts with FXN Asn151 as well as Zn 2+ coordinating ligand Asp71.…”

Section: Fxn Interactions With Nfs1 Dimer Interface and C-terminus Fmentioning

confidence: 99%

Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism

Fox

Feng

et al. 2019

Preprint

View full text Add to dashboard Cite

Iron-sulfur clusters (ISC) are essential in all life forms and carry out many crucial cellular functions.The core machinery for de novo ISC biosynthesis, located in the mitochondria matrix, is a fiveprotein complex containing the cysteine desulfurase NFS1 that is activated by frataxin (FXN), scaffold protein ISCU, accessory protein ISD11, and acyl-carrier protein ACP. Deficiency in FXN leads to the loss-of-function neurodegenerative disorder Friedreich's ataxia (FRDA). Recently crystal structures depicting the inactive 3-and 4-way sub-complexes of the ISC biosynthesis machinery, lacking the key activator FXN, have been determined. Here, the 3.2 Å resolution cryo-electron microscopy structure of the FXN-bound active human complex, containing two copies of the NFS1-ISD11-ACP-ISCU-FXN hetero-pentamer, delineates for the first time in any organism the interactions of FXN with the component proteins. FXN binds at the interface of two NFS1 and one ISCU subunits, modifying the local environment of a bound zinc ion that would otherwise inhibit NFS1 activity in complexes without FXN. Our structure sheds light on how FXN facilitates ISC production through unlocking the zinc inhibition and stabilizing key loop conformations of NFS1 and ISCU at the protein-protein interfaces, and offers an explanation of how FRDA clinical mutations affect complex formation and FXN activation.

show abstract

“…His86 is not included in most of the frataxin structures that are found in the protein data bank nor is conserved in yeast and bacterial homologues. More recently, while using NMR to investigate iron binding, it was also proposed that frataxin tightly binds a single Fe 2+ but not Fe 3+ [ 22 ].…”

Section: Frataxin Functionmentioning

confidence: 99%

Iron in Friedreich Ataxia: A Central Role in the Pathophysiology or an Epiphenomenon?

et al. 2018

View full text Add to dashboard Cite

Friedreich ataxia is a neurodegenerative disease with an autosomal recessive inheritance. In most patients, the disease is caused by the presence of trinucleotide GAA expansions in the first intron of the frataxin gene. These expansions cause the decreased expression of this mitochondrial protein. Many evidences indicate that frataxin deficiency causes the deregulation of cellular iron homeostasis. In this review, we will discuss several hypotheses proposed for frataxin function, their caveats, and how they could provide an explanation for the deregulation of iron homeostasis found in frataxin-deficient cells. We will also focus on the potential mechanisms causing cellular dysfunction in Friedreich Ataxia and on the potential use of the iron chelator deferiprone as a therapeutic agent for this disease.

show abstract

Interactions of iron-bound frataxin with ISCU and ferredoxin on the cysteine desulfurase complex leading to Fe-S cluster assembly

Cited by 52 publications

References 69 publications

Characterization of human frataxin missense variants in cancer tissues

Characterization of human frataxin missense variants in cancer tissues

Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism

Iron in Friedreich Ataxia: A Central Role in the Pathophysiology or an Epiphenomenon?

Contact Info

Product

Resources

About