High impact information on NFS1

• We show that Isd11 forms a stable complex with Nfs1, the cysteine desulfurase of the mitochondrial machinery for Fe/S cluster assembly [1].
• We propose that Isd11 acts together with Nfs1 in an early step in the biogenesis of Fe/S proteins [1].
• The ATP-binding cassette (ABC) transporter Atm1p of the mitochondrial inner membrane performs an essential function only in the generation of cytosolic Fe/S proteins by mediating export of Fe/S cluster precursors synthesized by Nfs1p and other mitochondrial proteins [2].
• 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 [3].
• However, this stimulatory effect of Ssq1p required neither ATP nor Jac1p and could be fully attributed to the activation of the Nfs1p desulfurase activity by Ssq1p [3].

Biological context of NFS1

• When this sequence was mutated to RRGSR, the mutant protein could not restore cell growth under chromosomal NFS1-depleted conditions [4].
• The third suppressor gene identified was NFS1 [5].
• The mutation mapped on chromosome III to an essential 1.5-kb open reading frame (L. S. Symington and T. D. Petes, Mol. Cell. Biol. 8:595-604, 1988), recently named NFS1 (S. G. Oliver et al., Nature [London] 357:38-46, 1992), located adjacent (centromere proximal) to LEU2 [6].
• Cysteine is utilized by the cysteine desulfurase Nfs1p to release sulfan sulfur; ATP presumably reflects the function of the Hsp70 family chaperone Ssq1p; and NADH is used for reduction of the ferredoxin Yah1p involved in Fe/S protein biogenesis [7].
• The results demonstrate that Nfs1 protein is required for the proper post-translational modification of the lipoamide-containing mitochondrial subproteome in yeast and pave the road toward a thorough understanding of its precise role in lipoic acid synthesis [8].

Anatomical context of NFS1

• When AUG1 of the yeast NFS1 gene was mutated to UUG and the resulting mRNA was translated in vitro using a reticulocyte system, initiation from the mutated codon was abolished and occurred instead at downstream codons at increased rates [9].
• The Nfs1 interacting protein Isd11 has an essential role in Fe/S cluster biogenesis in mitochondria [1].
• Nfs1p could not assemble an Fe/S cluster on the Isu scaffold proteins when they were located in the yeast cytosol [10].

Associations of NFS1 with chemical compounds

• In addition, upstream of the PaLEU2 the 3'-terminal half of a gene of the same orientation, encoding a homologue of the S. cerevisiae NFS1/SPL1 gene that encodes a mitochondrial cysteine desulphurase involved in both tRNA processing and mitochondrial metabolism, was found [11].
• This hypothesis was confirmed by experiments in which expression of wild-type Nfs1p from a regulated galactose-induced promoter was turned off, leading to recapitulation of the iron regulatory phenotypes characteristic of the MA14 mutant [12].
• Mass spectrometry analysis revealed an increase in 5-methoxycarbonylmethyluridine concomitant with a decrease in mcm(5)s(2)U in cy-tRNAs that were prepared from Nfs1p-depleted cells [13].

Other interactions of NFS1

• Taken together these results suggest a role for Ssq1p, Jac1p, and Nfs1p in assembly/maturation of mitochondrial iron-sulfur proteins and that one or more of the target Fe/S proteins contribute to oxidative damage in cells lacking copper/zinc SOD [5].

Analytical, diagnostic and therapeutic context of NFS1

• Comparison and identification of mitochondrial matrix proteins from wild-type and cysteine desulfurase-defective (nfs1-14, carrying a hypomorphic allele of NFS1) yeast strains, using two-dimensional gel electrophoresis coupled to mass spectrometry analyses, revealed large changes in the amounts of various proteins [8].

References