Structure of Yeast Sulfhydryl Oxidase Erv1 Reveals Electron Transfer of the Disulfide Relay System in the Mitochondrial Intermembrane Space

Guo, Pengchao; Ma, Jinming; Jiang, Yong-Liang; Wang, Shujie; Bao, Zhang-Zhi; Yu, Xiaojie; Chen, Yuxing; Zhou, Cong‐Zhao

doi:10.1074/jbc.m112.394759

Cited by 25 publications

(32 citation statements)

References 46 publications

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“…For example, the mutation may affect the interactions between Trp 183 (next to Arg 182 ) and other nearby aromatic residues (e.g. Trp 179 ) or, alternatively, it could affect the interaction between FAD and the aromatic residues that help in stabilizing it [6,9].…”

Section: Resultsmentioning

confidence: 99%

“…Because this arginine residue is conserved in other ALR homologues (Figure 1b), the authors also used yeast to show that the corresponding erv1 R182H mutant strain displayed genetic instability of the mtDNA, altered mitochondrial morphology, a temperature-sensitive growth phenotype and reduced cyt c oxidase (complex IV) activity [24]. Protein characterizations of human ALR have since then shown that the R194H mutation affects the thermal stability, FAD-binding and proteolysis The X-ray crystal structure of yeast S. cerevisiae Erv1 core domain residues 84-188 (c) and a zoomed in of the structure showing the hydrogen bond formed between Arg 182 and the 2 OH of the ribose moiety of FAD (d) (PDB code: 4EOH [9]). The structures were generated using the PyMOL software.…”

Section: Introductionmentioning

confidence: 99%

“…This FAD-binding domain acts as a catalytic core and contains a CXXC active-site disulfide located proximal to the iso-alloxazing ring of FAD, as well as a C-terminal CX 16 C structural disulfide [4][5][6][7][8]. The crystal structures of the FAD-binding domain of Erv1 portrayed it as a head-to-tail homodimer (PDB codes 4E0H and 3W4Y) where each subunit contains a four-helix bundle that harbours the FAD cofactor and an additional (H5) C-terminal single-turn helix (Figure 1c) [9]. Erv/ALR proteins also have a shuttle disulfide bond in a non-conserved range located on either the N-or the Cterminus of the FAD-binding domain.…”

Section: Introductionmentioning

confidence: 99%

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The disease-associated mutation of the mitochondrial thiol oxidase Erv1 impairs cofactor binding during its catalytic reaction

Ceh-Pavia

Ang

Spiller

et al. 2014

Biochemical Journal

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Erv1 (essential for respiration and viability 1) is an FADdependent thiol oxidase of the Erv/ALR (augmenter of liver regeneration) sub-family. It is an essential component of the mitochondrial import and assembly (MIA) pathway, playing an important role in the oxidative folding of the mitochondrial intermembrane space (IMS) proteins and linking the MIA pathway to the mitochondrial respiratory chain via cytochrome c (cyt c). The importance of the Erv/ALR enzymes was also demonstrated in a recent study where a single mutation in the human ALR (R194H) leads to autosomal recessive myopathy [Di Fonzo, Ronchi, Lodi, Fassone, Tigano, Lamperti, Corti, Bordoni, Fortunato, Nizzardo et al. (2009) Am. J. Hum. Genet. 84, 594-604]. However, the molecular mechanism of the disease is still unclear. In the present study, we use yeast Erv1 as a model to provide clear evidence for a progressive functional defect in the catalytic activity of the corresponding Erv1 R182H mutant. We show that the FAD cofactor was released from Erv1 R182H during its catalytic cycle, which led to the inactivation of the enzyme. We also characterized the effects of the mutation on the folding and stability of Erv1 and tested our in vitro findings in vivo using a yeast genetic approach. The results of the present study allow us to provide a model for the functional defect in Erv1 R182H, which could potentially be extended to human ALR R194H and provides insights into the molecular basis of autosomal recessive myopathy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The disease-associated mutation of the mitochondrial thiol oxidase Erv1 impairs cofactor binding during its catalytic reaction

Ceh-Pavia

Ang

Spiller

et al. 2014

Biochemical Journal

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“…The erv1-2 and erv1-5 strains each contain single point mutations in the ERV1 gene creating N166D and C159S substitutions, respectively (37). Asn-166 and Cys-159 are both located near the FAD binding site, with Cys-159 forming a structural disulfide with Cys-176 (36). As such, the C159S Erv1 mutant exhibits decreased FAD binding in vitro (38), whereas both erv1-2 and erv1-5 are impaired in import of IMS proteins (3,37,39).…”

Section: Resultsmentioning

confidence: 99%

Cytosolic Fe-S Cluster Protein Maturation and Iron Regulation Are Independent of the Mitochondrial Erv1/Mia40 Import System

Ozer

Dlouhy

Thornton

et al. 2015

Journal of Biological Chemistry

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Background:The mitochondrial sulfhydryl oxidase Erv1 is implicated in cytosolic iron-sulfur protein maturation and iron regulation. Results: An erv1 yeast strain used in previous iron metabolism studies is glutathione-deficient, and erv1/mia40 mutants with sufficient glutathione do not exhibit iron-related defects. Conclusion: Iron homeostasis is independent of Erv1/Mia40 function. Significance: The unexplained role of Erv1 in yeast iron metabolism is resolved.

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“…Such inter-subunit redox communication was also proposed for lfALR [24]. The structural aspects of the communication between Mia40 and Erv1p or ALR have received considerable attention [22, 24–26]. …”

Section: Introductionmentioning

confidence: 99%

Mia40 is a facile oxidant of unfolded reduced proteins but shows minimal isomerase activity

Hudson

Thorpe

2015

Archives of Biochemistry and Biophysics

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Mia40 participates in oxidative protein folding within the mitochondrial intermembrane space (IMS) by mediating the transfer of reducing equivalents from client proteins to FAD-linked oxidoreductases of the Erv1 family (lfALR in mammals). Here we investigate the specificity of the human Mia40/lfALR system towards non-cognate unfolded protein substrates to assess whether the efficient introduction of disulfides requires a particular amino acid sequence context or the presence of an IMS targeting signal. Reduced pancreatic ribonuclease A (rRNase), avian lysozyme, and riboflavin binding protein are all competent substrates of the Mia40/lfALR system, although they lack those sequence features previously thought to direct disulfide bond formation in cognate IMS substrates. The oxidation of rRNase by Mia40 does not limit overall turnover of unfolded substrate by the Mia40/lfALR system. Mia40 is an ineffective protein disulfide isomerase when its ability to restore enzymatic activity from scrambled RNase is compared to that of protein disulfide isomerase. Mia40’s ability to bind amphipathic peptides is evident by avid binding to the isolated B-chain during the insulin reductase assay. In aggregate these data suggest that the Mia40/lfALR system has a broad sequence specificity and that potential substrates may be protected from adventitious oxidation by kinetic sequestration within the mitochondrial IMS.

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Structure of Yeast Sulfhydryl Oxidase Erv1 Reveals Electron Transfer of the Disulfide Relay System in the Mitochondrial Intermembrane Space

Cited by 25 publications

References 46 publications

The disease-associated mutation of the mitochondrial thiol oxidase Erv1 impairs cofactor binding during its catalytic reaction

The disease-associated mutation of the mitochondrial thiol oxidase Erv1 impairs cofactor binding during its catalytic reaction

Cytosolic Fe-S Cluster Protein Maturation and Iron Regulation Are Independent of the Mitochondrial Erv1/Mia40 Import System

Mia40 is a facile oxidant of unfolded reduced proteins but shows minimal isomerase activity

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