Dataset Information

ISCU interacts with NFU1, and ISCU[4Fe-4S] transfers its Fe-S cluster to NFU1 leading to the production of holo-NFU1.

ABSTRACT: NFU1 is a late-acting factor in the biogenesis of human mitochondrial iron-sulfur proteins. Mutations in NFU1 are associated with genetic diseases such as multiple mitochondrial dysfunctions syndrome 1 (MMDS1) that involve defects in mitochondrial [4Fe-4S] proteins. We present results from NMR spectroscopy, small angle X-ray scattering, size exclusion chromatography, and isothermal titration calorimetry showing that the structured conformer of human ISCU binds human NFU1. The dissociation constant determined by ITC is K_d = 1.1 ± 0.2 μM. NMR and SAXS studies led to a structural model for the complex in which the cluster binding region of ISCU interacts with two α-helices in the C-terminal domain of NFU1. In vitro experiments demonstrate that ISCU[4Fe-4S] transfers its Fe-S cluster to apo-NFU1, in the absence of a chaperone, leading to the assembly of holo-NFU1. By contrast, the cluster of ISCU[2Fe-2S] remains bound to ISCU in the presence of apo-NFU1.

SUBMITTER: Cai K

PROVIDER: S-EPMC7261492 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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ISCU interacts with NFU1, and ISCU[4Fe-4S] transfers its Fe-S cluster to NFU1 leading to the production of holo-NFU1.

Cai Kai K Frederick Ronnie O RO Markley John L JL

Journal of structural biology 20200306 2

NFU1 is a late-acting factor in the biogenesis of human mitochondrial iron-sulfur proteins. Mutations in NFU1 are associated with genetic diseases such as multiple mitochondrial dysfunctions syndrome 1 (MMDS1) that involve defects in mitochondrial [4Fe-4S] proteins. We present results from NMR spectroscopy, small angle X-ray scattering, size exclusion chromatography, and isothermal titration calorimetry showing that the structured conformer of human ISCU binds human NFU1. The dissociation consta ...[more]

PMID: 32151725

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Project description:The all-ferrous, carbene-capped Fe(4)S(4) cluster, synthesized by Deng and Holm (DH complex), has been studied with density functional theory (DFT). The geometry of the complex was optimized for several electronic configurations. The lowest energy was obtained for the broken-symmetry (BS) configuration derived from the ferromagnetic state by reversing the spin projection of one of the high spin (S(i) = 2) irons. The optimized geometry of the latter configuration contains one unique and three equivalent iron sites, which are both structurally and electronically clearly distinguishable. For example, a distinctive feature of the unique iron site is the diagonal Fe···S distance, which is 0.3 Å longer than for the equivalent irons. The calculated (57)Fe hyperfine parameters show the same 1:3 pattern as observed in the Mössbauer spectra and are in good agreement with experiment. BS analysis of the exchange interactions in the optimized geometry for the 1:3, M(S) = 4, BS configuration confirms the prediction of an earlier study that the unique site is coupled to the three equivalent ones by strong antiferromagnetic exchange (J > 0 in J ?(j<4)?(4)·?(j)) and that the latter are mutually coupled by ferromagnetic exchange (J' < 0 in J' ?(i<j<4)?(i)·?(j)). In combination, these exchange couplings stabilize an S = 4 ground state in which the composite spin of the three equivalent sites (S(123) = 6) is antiparallel to the spin (S(4) = 2) of the unique site. Thus, DFT analysis supports the idea that the unprecedented high value of the spin of the DH complex and, by analogy, of the all-ferrous cluster of the Fe-protein of nitrogenase, results from a remarkably strong dependence of the exchange interactions on cluster core geometry. The structure dependence of the exchange-coupling constants in the Fe(II)-(?(3)-S)(2)-Fe(II) moieties of the all-ferrous clusters is compared with the magneto-structural correlations observed in the data for dinuclear copper complexes. Finally, we discuss two all-ferric clusters in the light of the results for the all-ferrous cluster.

Dataset Information

ISCU interacts with NFU1, and ISCU[4Fe-4S] transfers its Fe-S cluster to NFU1 leading to the production of holo-NFU1.

Publications

ISCU interacts with NFU1, and ISCU[4Fe-4S] transfers its Fe-S cluster to NFU1 leading to the production of holo-NFU1.

Similar Datasets

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