Disease relevance of ISU1

• Immunoblotting studies using an antibody directed against Escherichia coli IscU reveal that both Isu1p and Isu2p are localized primarily in the mitochondria and that Isu1p is the predominant form expressed under all growth conditions tested [1].

High impact information on ISU1

• The mitochondrial proteins Isu1p and Isu2p play an essential role in the maturation of cellular iron-sulfur (Fe/S) proteins in eukaryotes [2].
• In contrast, depletion of the Hsp70 chaperone Ssq1p, its co-chaperone Jac1p or the glutaredoxin Grx5p markedly increased the amount of Fe/S clusters bound to Isu1p, even though these mitochondrial proteins are crucial for maturation of Fe/S proteins [2].
• We suggest that NFU1 and ISU1 gene products play a role in iron homeostasis, perhaps in assembly, insertion, and/or repair of mitochondrial Fe-S clusters [3].
• Quantitative RT-PCR studies confirmed the significant down-regulation of Isu1, CPOX and ferrochelatase at 10 weeks in mouse hearts [4].
• We were unable to mislocalize Isu1p to the cytosol due to the presence of multiple, independent mitochondrial targeting signals in this protein [5].

Biological context of ISU1

• FRR3 was found to be homologous to ISU1 and ISU2 of S. cerevisiae, which form mitochondrial iron-sulfur complexes; FRR4 was found to be homologous to YFH1, the yeast frataxin homologue, which also participates in iron-sulfur cluster biogenesis [6].
• Finally, we have demonstrated through cross-linking studies that ferredoxin, an electron-transport protein, forms a complex with ISU1 in both apo and holo states [7].
• In the absence of chaperones, the kinetics of Fe/S cluster formation on Isu1p were compatible with a chemical reconstitution pathway with Nfs1p functioning as a sulfide donor [8].

Anatomical context of ISU1

• The mature forms of His-tagged wild-type and D37A Schizosaccharomyces pombe ISU1 were cloned and overexpressed as inclusion bodies in Escherichia coli [7].

Associations of ISU1 with chemical compounds

• Using a spectroscopic assay, we have analyzed the potential role of the chaperones in Fe/S cluster assembly on the scaffold protein Isu1p in vitro in the presence of the cysteine desulfurase Nfs1p [8].
• Here, we show that a marked change in the electrostatic properties of a specific region of Yfh1 surface-by substituting two or four acidic residues by lysine or alanine, respectively-impairs Fe-S cluster assembly, weakens the interaction between Yfh1 and Isu1, and increases oxidative damage [9].

Physical interactions of ISU1

• Consistent with this idea, these Isu1p mutants were capable of binding an Fe/S cluster in vivo but failed to restore the growth and Fe/S cluster assembly defects of a Isu1p/Isu2p-deficient yeast strain [8].

Other interactions of ISU1

• They have been designated ISU1 and ISU2 [3].
• Characterization of the interaction between the J-protein Jac1p and the scaffold for Fe-S cluster biogenesis, Isu1p [10].
• Taken together, these data suggest that Ssq1p/Jac1p/Mge1p are not important for Fe/S cluster synthesis on Isu1p [8].

Analytical, diagnostic and therapeutic context of ISU1

• UV-vis absorption and Mössbauer spectroscopies (delta = 0.29 +/- 0.05 mm/s; DeltaE(Q) = 0.59 +/- 0.05 mm/s) were used to characterize D37A ISU1 and show the presence of [2Fe-2S](2+) clusters in each subunit [7].

References