Mammalian iron–sulphur proteins: novel insights into biogenesis and function

Rouault, Tracey A.

doi:10.1038/nrm3909

Cited by 175 publications

(168 citation statements)

References 111 publications

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“…NBIA diseases also include neuroferritinopathy, aceruloplasminemia, beta-propeller protein-associated neurodegeneration, and a number of inherited diseases [43,47,48]. The incidence of NBIA disease continues to increase and clearly shows the importance of understanding iron metabolism and its potential link to neuronal loss.…”

Section: Neurodegenerative Diseases Linked To Ironmentioning

confidence: 99%

Iron, Aging, and Neurodegeneration

Angelova

Brown

2015

Metals

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Abstract:Iron is a trace element of considerable interest to both chemistry and biology. In a biological context its chemistry is vital to the roles it performs. However, that same chemistry can contribute to a more deleterious role in a variety of diseases. The brain is a very sensitive organ due to the irreplaceable nature of neurons. In this regard regulation of brain iron chemistry is essential to maintaining neuronal viability. During the course of normal aging, the brain changes the way it deals with iron and this can contribute to its susceptibility to disease. Additionally, many of the known neurodegenerative diseases have been shown to be influenced by changes in brain iron. This review examines the role of iron in the brain and neurodegenerative diseases and the potential role of changes in brain iron caused by aging.

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Section: Neurodegenerative Diseases Linked To Ironmentioning

confidence: 99%

Iron, Aging, and Neurodegeneration

Angelova

Brown

2015

Metals

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“…At the center of the complex, the pyridoxal 5′-phosphate (PLP)-dependent cysteine desulfurase NFS1 forms a tight complex with ISD11 (4,8,9,27). The NFS1-ISD11 complex catalyzes the conversion of L-cysteine to L-alanine and generates a persulfide intermediate on a cysteine of the mobile S-transfer loop of NFS1 (S-loop) (24,28). The terminal sulfur of this intermediate is transferred to the scaffold protein ISCU2, where it is combined with ferrous iron and electrons, from a ferredoxin (29,30), to form Fe-S clusters.…”

Section: Significancementioning

confidence: 99%

Structure of human Fe–S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP–ISD11 interactions

Cory

Vranken

Brignole

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

142

228

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In eukaryotes, sulfur is mobilized for incorporation into multiple biosynthetic pathways by a cysteine desulfurase complex that consists of a catalytic subunit (NFS1), LYR protein (ISD11), and acyl carrier protein (ACP). This NFS1-ISD11-ACP (SDA) complex forms the core of the iron-sulfur (Fe-S) assembly complex and associates with assembly proteins ISCU2, frataxin (FXN), and ferredoxin to synthesize Fe-S clusters. Here we present crystallographic and electron microscopic structures of the SDA complex coupled to enzyme kinetic and cell-based studies to provide structure-function properties of a mitochondrial cysteine desulfurase. Unlike prokaryotic cysteine desulfurases, the SDA structure adopts an unexpected architecture in which a pair of ISD11 subunits form the dimeric core of the SDA complex, which clarifies the critical role of ISD11 in eukaryotic assemblies. The different quaternary structure results in an incompletely formed substrate channel and solvent-exposed pyridoxal 5′-phosphate cofactor and provides a rationale for the allosteric activator function of FXN in eukaryotic systems. The structure also reveals the 4′-phosphopantetheine-conjugated acyl-group of ACP occupies the hydrophobic core of ISD11, explaining the basis of ACP stabilization. The unexpected architecture for the SDA complex provides a framework for understanding interactions with acceptor proteins for sulfur-containing biosynthetic pathways, elucidating mechanistic details of eukaryotic Fe-S cluster biosynthesis, and clarifying how defects in Fe-S cluster assembly lead to diseases such as Friedreich's ataxia. Moreover, our results support a lock-and-key model in which LYR proteins associate with acyl-ACP as a mechanism for fatty acid biosynthesis to coordinate the expression, Fe-S cofactor maturation, and activity of the respiratory complexes.ron-sulfur (Fe-S) clusters are protein cofactors and are required for critical biological processes such as oxidative respiration, nitrogen fixation, and photosynthesis. The iron-sulfur cluster (ISC) biosynthetic pathway, which is found in most prokaryotes and in the mitochondrial matrix of eukaryotes, is responsible for the synthesis of Fe-S clusters and distribution of these cofactors to the appropriate target proteins. Despite the homology between analogous components of the prokaryotic and eukaryotic ISC pathways, there are key unexplained differences, such as the requirement of the LYR protein ISD11 and acyl carrier protein (ACP) for function in eukaryotic but not prokaryotic ISC systems (1, 2).Mitochondrial LYR proteins are members of a recently identified superfamily that are characterized by their small size (10-22 kDa), high positive charge, invariant Phe residue, and eponymous LeuTyr-Arg (LYR) motif near their N terminus (3). LYR proteins function as subunits or assembly factors for respiratory complexes I, II, III, and V. Human LYRM4, also known as ISD11, is critical for the function of the Fe-S assembly complex (4-9), whereas LYRM8, a key maturation factor for mitochondrial complex II, ...

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“…A group of dedicated proteins are responsible for iron-sulfur cluster biogenesis (19). In E. coli, there are two iron-sulfur cluster assembly systems, the housekeeping iscSUA-hscBA-fdx gene cluster (20), which is conserved from prokaryotes (bacteria) to eukaryotes (18,21), and the inducible sufABCDSE gene cluster (22), which represents a redundant activity of iscSUA-hscBA-fdx and is found only in plastids in plants, archaea, and some bacteria (23). Among the proteins encoded by iscSUA-hscBA-fdx, IscS is a pyridoxal 5= phosphate-dependent cysteine desulfurase that provides sulfide for iron-sulfur cluster assembly (24).…”

mentioning

confidence: 99%

Anaerobic Copper Toxicity and Iron-Sulfur Cluster Biogenesis in Escherichia coli

Tan

Yang

Tang

et al. 2017

Appl Environ Microbiol

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While copper is an essential trace element in biology, pollution of groundwater from copper has become a threat to all living organisms. Cellular mechanisms underlying copper toxicity, however, are still not fully understood. Previous studies have shown that iron-sulfur proteins are among the primary targets of copper toxicity in Escherichia coli under aerobic conditions. Here, we report that, under anaerobic conditions, iron-sulfur proteins in E. coli cells are even more susceptible to copper in medium. Whereas addition of 0.2 mM copper(II) chloride to LB (Luria-Bertani) medium has very little or no effect on iron-sulfur proteins in wild-type E. coli cells under aerobic conditions, the same copper treatment largely inactivates iron-sulfur proteins by blocking iron-sulfur cluster biogenesis in the cells under anaerobic conditions. Importantly, proteins that do not have iron-sulfur clusters (e.g., fumarase C and cysteine desulfurase) in E. coli cells are not significantly affected by copper treatment under aerobic or anaerobic conditions, indicating that copper may specifically target iron-sulfur proteins in cells. Additional studies revealed that E. coli cells accumulate more intracellular copper under anaerobic conditions than under aerobic conditions and that the elevated copper content binds to the iron-sulfur cluster assembly proteins IscU and IscA, which effectively inhibits iron-sulfur cluster biogenesis. The results suggest that the copper-mediated inhibition of iron-sulfur proteins does not require oxygen and that iron-sulfur cluster biogenesis is the primary target of anaerobic copper toxicity in cells.IMPORTANCE Copper contamination in groundwater has become a threat to all living organisms. However, cellular mechanisms underlying copper toxicity have not been fully understood up to now. The work described here reveals that iron-sulfur proteins in Escherichia coli cells are much more susceptible to copper in medium under anaerobic conditions than they are under aerobic conditions. Under anaerobic conditions, E. coli cells accumulate excess intracellular copper, which specifically targets iron-sulfur proteins by blocking iron-sulfur cluster biogenesis. Since iron-sulfur proteins are involved in diverse and vital physiological processes, inhibition of ironsulfur cluster biogenesis by copper disrupts multiple cellular functions and ultimately inhibits cell growth. The results from this study illustrate a new interplay between intracellular copper toxicity and iron-sulfur cluster biogenesis in bacterial cells under anaerobic conditions.

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Mammalian iron–sulphur proteins: novel insights into biogenesis and function

Cited by 175 publications

References 111 publications

Iron, Aging, and Neurodegeneration

Iron, Aging, and Neurodegeneration

Structure of human Fe–S assembly subcomplex reveals unexpected cysteine desulfurase architecture and acyl-ACP–ISD11 interactions

Anaerobic Copper Toxicity and Iron-Sulfur Cluster Biogenesis in Escherichia coli

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