Structure and functional dynamics of the mitochondrial Fe/S cluster synthesis complex

Boniecki, Michal T.; Freibert, Sven‐Andreas; Mühlenhoff, Ulrich; Lill, Roland; Cygler, Mirosław

doi:10.1038/s41467-017-01497-1

Cited by 159 publications

(293 citation statements)

References 67 publications

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“…In the current working model, a [2Fe–2S] cluster is de novo synthesized on the scaffold protein ISCU2 by a high molecular weight complex (HMW complex hereafter), composed of five proteins (ISCU2, NFS1, frataxin, ISD11 and the acyl carrier protein) [133–135]. On the basis of yeast in vivo data [136–138], it has been proposed that the subsequent step in the human ISC assembly process consists of the transfer of the newly synthetized cluster to the mitochondrial monothiol glutaredoxin, GLRX5, which acts as a Fe–S cluster transfer protein, inserting the cluster into mitochondrial [2Fe–2S] protein targets.…”

Section: The Contribution Of Solution Nmr To Understand Molecular Aspmentioning

confidence: 99%

The NMR contribution to protein–protein networking in Fe–S protein maturation

et al. 2018

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Iron–sulfur proteins were among the first class of metalloproteins that were actively studied using NMR spectroscopy tailored to paramagnetic systems. The hyperfine shifts, their temperature dependencies and the relaxation rates of nuclei of cluster-bound residues are an efficient fingerprint of the nature and the oxidation state of the Fe–S cluster. NMR significantly contributed to the analysis of the magnetic coupling patterns and to the understanding of the electronic structure occurring in [2Fe–2S], [3Fe–4S] and [4Fe–4S] clusters bound to proteins. After the first NMR structure of a paramagnetic protein was obtained for the reduced E. halophila HiPIP I, many NMR structures were determined for several Fe–S proteins in different oxidation states. It was found that differences in chemical shifts, in patterns of unobserved residues, in internal mobility and in thermodynamic stability are suitable data to map subtle changes between the two different oxidation states of the protein. Recently, the interaction networks responsible for maturing human mitochondrial and cytosolic Fe–S proteins have been largely characterized by combining solution NMR standard experiments with those tailored to paramagnetic systems. We show here the contribution of solution NMR in providing a detailed molecular view of “Fe–S interactomics”. This contribution was particularly effective when protein–protein interactions are weak and transient, and thus difficult to be characterized at high resolution with other methodologies.

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Section: The Contribution Of Solution Nmr To Understand Molecular Aspmentioning

confidence: 99%

The NMR contribution to protein–protein networking in Fe–S protein maturation

et al. 2018

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“…This conserved residue was recognized to be an important residue for the hydrogen bond formation between NFS1 and ISD11 [10, 11]. The first subject presented at 7 months of age with lethargy, myocardial failure, and generalized seizures during an infectious episode ultimately leading to fatal outcome 3 days later.…”

Section: Mitochondrial Iron–sulfur Biosynthesis (Isc)mentioning

confidence: 99%

Clinical and genetic aspects of defects in the mitochondrial iron–sulfur cluster synthesis pathway

Vanlander

Coster

2018

J Biol Inorg Chem

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Iron–sulfur clusters are evolutionarily conserved biological structures which play an important role as cofactor for multiple enzymes in eukaryotic cells. The biosynthesis pathways of the iron–sulfur clusters are located in the mitochondria and in the cytosol. The mitochondrial iron–sulfur cluster biosynthesis pathway (ISC) can be divided into at least twenty enzymatic steps. Since the description of frataxin deficiency as the cause of Friedreich’s ataxia, multiple other deficiencies in ISC biosynthesis pathway have been reported. In this paper, an overview is given of the clinical, biochemical and genetic aspects reported in humans affected by a defect in iron–sulfur cluster biosynthesis.

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“…We determined the stoichiometry of the cysteine desulfurase complex as [NFS1] 2 :[ISD11] 2 :[Acp] 2 [13], hence-forth abbreviated as “(NIA) 2 ”. The presence of E. coli Acp and this stoichiometry has been confirmed by recent X-ray structures of (NIA) 2 complexes produced by co-expressing human ISD11 and NFS1 in E. coli cells [15,16]. …”

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confidence: 66%

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

Cai

Frederick

Tonelli

et al. 2018

Journal of Inorganic Biochemistry

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Frataxin (FXN) is involved in mitochondrial iron-sulfur (Fe-S) cluster biogenesis and serves to accelerate Fe-S cluster formation. FXN deficiency is associated with Friedreich ataxia, a neurodegenerative disease. We have used a combination of isothermal titration calorimetry and multinuclear NMR spectroscopy to investigate interactions among the components of the biological machine that carries out the assembly of iron-sulfur clusters in human mitochondria. Our results show that FXN tightly binds a single Fe2+ but not Fe3+. While FXN (with or without bound Fe2+) does not bind the scaffold protein ISCU directly, the two proteins interact mutually when each is bound to the cysteine desulfurase complex ([NFS1]2:[ISD11]2:[Acp]2), abbreviated as (NIA)2, where “N” represents the cysteine desulfurase (NFS1), “I” represents the accessory protein (ISD11), and “A” represents acyl carrier protein (Acp). FXN binds (NIA)2 weakly in the absence of ISCU but more strongly in its presence. Fe2+-FXN binds to the (NIA)2-ISCU2 complex without release of iron. However, upon the addition of both L-cysteine and a reductant (either reduced FDX2 or DTT), Fe2+ is released from FXN as consistent with Fe2+-FXN being the proximal source of iron for Fe-S cluster assembly.

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Structure and functional dynamics of the mitochondrial Fe/S cluster synthesis complex

Cited by 159 publications

References 67 publications

The NMR contribution to protein–protein networking in Fe–S protein maturation

The NMR contribution to protein–protein networking in Fe–S protein maturation

Clinical and genetic aspects of defects in the mitochondrial iron–sulfur cluster synthesis pathway

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

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