Cochaperone Binding to LYR Motifs Confers Specificity of Iron Sulfur Cluster Delivery

Maio, Nunziata; Singh, Anamika; Uhrigshardt, Helge; Saxena, Neetu; Tong, Wing-Hang; Rouault, Tracey A.

doi:10.1016/j.cmet.2014.01.015

Cited by 148 publications

(280 citation statements)

References 51 publications

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“…5B). Recent affinity capture MS studies further support this hypothesis by providing evidence that ACP interacts with at least 7 of the 11 human LYR proteins (67,68), including LYR proteins that also interact with HSC20 and are implicated in the Fe-S cluster delivery mechanism (10,69). These results suggest that the LYR superfamily forms lock-and-key interactions with ACP-associated 4′-PPTconjugated fatty acids that influence or control their maturation and function.…”

Section: Discussionsupporting

confidence: 50%

“…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, interacts with the HSC20 chaperone (10), which is important for Fe-S cluster delivery to apo targets. Despite their vital roles in Fe-S cluster cofactor biogenesis and oxidative respiration, structurefunction details for these LYR proteins are poorly understood.…”

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confidence: 99%

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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.

139

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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Section: Discussionsupporting

confidence: 50%

mentioning

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.

139

228

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“…These data suggest that substrate recognition of XPD by the CIA targeting complex likely occurs in a bipartite manner in which the CIA targeting complex is first recruited to XPD via a distal docking sequence that then facilitates the insertion of an Fe-S cluster into the Fe-S cluster binding domain of XPD. Apoprotein recognition in this manner is reminiscent of the recognition of LYR motifs in mitochondrial Fe-S recipients by the co-chaperone HSC20 and may suggest a general paradigm for Fe-S protein recognition (23). However, the extent to which docking sequence-dependent recognition of apoXPD by the CIA targeting complex can be generalized to other Fe-S proteins remains unclear.…”

Section: Discussionmentioning

confidence: 99%

The Association of the Xeroderma Pigmentosum Group D DNA Helicase (XPD) with Transcription Factor IIH Is Regulated by the Cytosolic Iron-Sulfur Cluster Assembly Pathway

Vashisht

Sharma

et al. 2015

Journal of Biological Chemistry

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Background:The mechanism by which XPD helicase acquires its Fe-S cluster is unknown. Results: XPD associates with the CIA targeting complex or TFIIH in two mutually exclusive protein complexes. Blocking Fe-S cluster assembly on XPD inhibits its incorporation into TFIIH. Conclusion: XPD maturation is a stepwise process in which XPD acquires its Fe-S cluster before binding TFIIH. Significance: The XPD-CIA targeting complex interaction is required for TFIIH assembly.

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“…Of the nine further mitochondrial LYR proteins known (21), one interacts with the L-cysteine desulfurase for FeS cluster and respiratory chain biogenesis (30), and several function as respiratory chain assembly factors (21,31). The LYR motif may recruit the apparatus for FeS cluster insertion to complex II (mitochondrial succinate:ubiquinone oxidoreductase), and it has been suggested that LYR motifs in general may be used to identify new FeS-containing proteins (32). Neither of the LYRcomplex I subunits are FeS proteins; B14 is bound to the FeScontaining hydrophilic arm of complex I but B22 is very distant from it.…”

Section: Discussionmentioning

confidence: 99%

Structure of subcomplex Iβ of mammalian respiratory complex I leads to new supernumerary subunit assignments

Zhu

King

et al. 2015

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

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Mitochondrial complex I (proton-pumping NADH:ubiquinone oxidoreductase) is an essential respiratory enzyme. Mammalian complex I contains 45 subunits: 14 conserved "core" subunits and 31 "supernumerary" subunits. The structure of Bos taurus complex I, determined to 5-Å resolution by electron cryomicroscopy, described the structure of the mammalian core enzyme and allowed the assignment of 14 supernumerary subunits. Here, we describe the 6.8-Å resolution X-ray crystallography structure of subcomplex Iβ, a large portion of the membrane domain of B. taurus complex I that contains two core subunits and a cohort of supernumerary subunits. By comparing the structures and composition of subcomplex Iβ and complex I, supported by comparisons with Yarrowia lipolytica complex I, we propose assignments for eight further supernumerary subunits in the structure. Our new assignments include two CHCH-domain containing subunits that contain disulfide bridges between CX 9 C motifs; they are processed by the Mia40 oxidative-folding pathway in the intermembrane space and probably stabilize the membrane domain. We also assign subunit B22, an LYR protein, to the matrix face of the membrane domain. We reveal that subunit B22 anchors an acyl carrier protein (ACP) to the complex, replicating the LYR protein-ACP structural module that was identified previously in the hydrophilic domain. Thus, we significantly extend knowledge of how the mammalian supernumerary subunits are arranged around the core enzyme, and provide insights into their roles in biogenesis and regulation.CHCH domain | electron transport chain | LYR protein | mitochondria | NADH:ubiquinone oxidoreductase I n mammalian mitochondria, respiratory complex I (NADH: ubiquinone oxidoreductase) (1, 2) contains 45 subunits with a combined mass of 1 MDa (3-6). Fourteen core subunits, conserved from bacteria to humans, constitute the minimal complex I and catalyze the energy transducing reaction: NADH oxidation and ubiquinone reduction coupled to proton translocation across the inner membrane. Complex I is thus critical for mammalian metabolism: it oxidizes the NADH generated by the tricarboxylic acid cycle and β-oxidation, produces ubiquinol for the rest of the respiratory chain, and contributes to the proton-motive force that supports ATP synthesis and transport processes. Seven of the core subunits are hydrophilic proteins that are encoded in the nucleus and imported to mitochondria, and the other seven are hydrophobic, membrane-bound proteins (known as the ND subunits) that are encoded by the mitochondrial genome. These two sets of seven subunits form the two major domains of complex I, in the matrix and inner membrane, which confer its characteristic L shape.The protein composition of complex I from Bos taurus heart mitochondria has been characterized extensively, and is the blueprint for the human enzyme (3-6). In addition to the 14 core subunits it contains 31 supernumerary subunits (including two copies of the acyl-carrier protein, SDAP; ref. 2). Several supernumerary subunit...

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Cochaperone Binding to LYR Motifs Confers Specificity of Iron Sulfur Cluster Delivery

Cited by 148 publications

References 51 publications

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

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

The Association of the Xeroderma Pigmentosum Group D DNA Helicase (XPD) with Transcription Factor IIH Is Regulated by the Cytosolic Iron-Sulfur Cluster Assembly Pathway

Structure of subcomplex Iβ of mammalian respiratory complex I leads to new supernumerary subunit assignments

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