Maturation of Iron-Sulfur Proteins in Eukaryotes: Mechanisms, Connected Processes, and Diseases

Abstract

Iron-sulfur (Fe/S) proteins are involved in a wide variety of cellular processes such as enzymatic reactions, respiration, cofactor biosynthesis, ribosome biogenesis, regulation of gene expression, and DNA-RNA metabolism. Assembly of Fe/S clusters, small inorganic cofactors, is assisted by complex proteinaceous machineries, which use cysteine as a source of sulfur, combine it with iron to synthesize an Fe/S cluster on scaffold proteins, and finally incorporate the cluster into recipient apoproteins. In eukaryotes, such as yeast and human cells, more than 20 components are known that facilitate the maturation of Fe/S proteins in mitochondria, cytosol, and nucleus. These biogenesis components also perform crucial roles in other cellular pathways, e.g., in the regulation of iron homeostasis or the modification of tRNA. Numerous diseases including several neurodegenerative and hematological disorders have been associated with defects in Fe/S protein biogenesis, underlining the central importance of this process for life.

Analysis of iron–sulfur protein maturation in eukaryotes

“…Despite the chemical simplicity of Fe/S clusters, their biosynthesis and insertion into apoproteins within cells require dedicated and complex machinery 2,3 . On the basis of the identification of proteins responsible for the biosynthesis of bacterial Fe/S enzymes, 2,4 a related ISC assembly machinery has been discovered in mitochondria of eukaryotes.…”

“…In Baker's yeast, the best-studied eukaryote for this process, 15 proteins are known as members of the mitochondrial ISC assembly machinery (for recent reviews, see refs. 3,5). The key players are the cysteine desulfurase complex Nfs1/Isd11, which supplies sulfur to the scaffold protein Isu1 on which an Fe/S cluster is assembled de novo (see Fig.…”

“…1) (ref. 3). This biosynthetic step requires the redox chain NADH-ferredoxin reductase (Arh1)-ferredoxin (Yah1) and the putative iron donor frataxin (Yfh1).…”

“…The crucial importance of Fe/S proteins and their assembly machineries has been recognized by virtue of the association of lesions in ISC machinery genes with three human diseases (for a review, see refs. 3,24). First, a GAA triplet repeat expansion in an intronic region of frataxin is the most frequent cause of Friedreich ataxia, an autosomal recessive neurodegenerative disorder 25 .…”

Ferric ion (hydr)oxo clusters in the “Venus flytrap” cleft of FbpA: Mössbauer, calorimetric and mass spectrometric studies

“…In general, proteins having non-heme polynuclear iron sites play important roles in a plethora of important physiological reactions including oxygen transport, oxygenases and hydrogenases [11][12][13][14][15][16][17]. Recently it has been shown that a phosphate uptake and transfer protein (Pho U)…”