Erv1 Mediates the Mia40-dependent Protein Import Pathway and Provides a Functional Link to the Respiratory Chain by Shuttling Electrons to Cytochrome c

Allen, Simon; Balabanidou, Vasileia; Sideris, Dionisia P.; Lisowsky, Thomas; Tokatlidis, Kostas

doi:10.1016/j.jmb.2005.08.049

Cited by 208 publications

(199 citation statements)

References 41 publications

(55 reference statements)

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“…The intermembrane space (IMS) between the outer and inner mitochondrial membranes contains many proteins with a molecular mass Ͻ20 kDa and characteristic cysteine motifs. Import of those small cysteine-containing proteins is driven by a redox-regulated translocator Tim40/Mia40 (4-6) and its partner proteins including Erv1 (7,8) and Hot13 (9,10).…”

Section: Structural Basis Of Yeast Tim40/mia40 As An Oxidative Translmentioning

confidence: 99%

Structural basis of yeast Tim40/Mia40 as an oxidative translocator in the mitochondrial intermembrane space

Kawano

Yamano²,

Naoé³

et al. 2009

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

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The mitochondrial intermembrane space (IMS) contains many small cysteine-bearing proteins, and their passage across the outer membrane and subsequent folding require recognition and disulfide bond transfer by an oxidative translocator Tim40/Mia40 in the inner membrane facing the IMS. Here we determined the crystal structure of the core domain of yeast Mia40 (Mia40C4) as a fusion protein with maltose-binding protein at a resolution of 3 Å. The overall structure of Mia40C4 is a fruit-dish-like shape with a hydrophobic concave region, which accommodates a linker segment of the fusion protein in a helical conformation, likely mimicking a bound substrate. Replacement of the hydrophobic residues in this region resulted in growth defects and impaired assembly of a substrate protein. The Cys296-Cys298 disulfide bond is close to the hydrophobic concave region or possible substrate-binding site, so that it can mediate disulfide bond transfer to substrate proteins. These results are consistent with the growth phenotypes of Mia40 mutant cells containing Ser replacement of the conserved cysteine residues.

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Section: Structural Basis Of Yeast Tim40/mia40 As An Oxidative Translmentioning

confidence: 99%

Structural basis of yeast Tim40/Mia40 as an oxidative translocator in the mitochondrial intermembrane space

Kawano

Yamano²,

Naoé³

et al. 2009

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

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“…In addition, depletion of Erv1p from cells led to accumulation of Mia40p, which had the residues Cys-1 and Cys-2 present in the reduced state (15). Moreover, Tokatlidis and co-workers (17) have reported that Erv1p did not directly oxidize small Tim proteins, substrates of the Mia40p translocation pathway containing twin CX 3 C motifs. Mia40p might not be the only substrate of Erv1p in the IMS of mitochondria, since there are, in addition to proteins with twin CX n C motifs, other proteins containing disulfide bonds.…”

Section: Discussionmentioning

confidence: 99%

“…The disulfide bond in Erv1p is recovered by electron transfer to the FAD bound to Erv1p. Oxidized FAD appears to be recovered by the transfer of electrons to cytochrome c (17,38). In the future the detailed analysis of reaction intermediates will be important to refine the model.…”

Section: Discussionmentioning

confidence: 99%

“…By a subsequent proteolytic step the mature protein is released into the IMS. On the other hand, there are many proteins of relatively small size that lack presequences but contain motifs of conserved cysteine residues, such as the twin CX 9 C motif in the copper chaperone Cox17p and in Cox19p, Mdm35p, Mic14p, and Mic17p or the twin CX 3 C motif in the family of small Tim proteins (6 -11).ProteinswithtwinCX n CmotifsusetheMia40p-dependent translocation pathway, which consists of at least two components in the IMS, Mia40p and Erv1p (8,(12)(13)(14)(15)(16)(17). Both proteins are essential for viability of yeast cells (12-14, 18 -20).…”

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confidence: 99%

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Functional Characterization of Mia40p, the Central Component of the Disulfide Relay System of the Mitochondrial Intermembrane Space

Grumbt

Stroobant

Terziyska

et al. 2007

Journal of Biological Chemistry

116

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Mia40p and Erv1p are components of a translocation pathway for the import of cysteine-rich proteins into the intermembrane space of mitochondria. We have characterized the redox behavior of Mia40p and reconstituted the disulfide transfer system of Mia40p by using recombinant functional C-terminal fragment of Mia40p, Mia40C, and Erv1p. Oxidized Mia40p contains three intramolecular disulfide bonds. One disulfide bond connects the first two cysteine residues in the CPC motif. The second and the third bonds belong to the twin CX 9 C motif and bridge the cysteine residues of two CX 9 C segments. In contrast to the stabilizing disulfide bonds of the twin CX 9 C motif, the first disulfide bond was easily accessible to reducing agents. Partially reduced Mia40C generated by opening of this bond as well as fully reduced Mia40C were oxidized by Erv1p in vitro. In the course of this reaction, mixed disulfides of Mia40C and Erv1p were formed. Reoxidation of fully reduced Mia40C required the presence of the first two cysteine residues in Mia40C. However, efficient reoxidation of a Mia40C variant containing only the cysteine residues of the twin CX 9 C motif was observed when in addition to Erv1p low amounts of wild type Mia40C were present. In the reconstituted system the thiol oxidase Erv1p was sufficient to transfer disulfide bonds to Mia40C, which then could oxidize the variant of Mia40C. In summary, we reconstituted a disulfide relay system consisting of Mia40C and Erv1p.

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“…After translocation through the TOM complex, small Tims are captured in a disulphide bondlinked intermediate with the intermembrane space oxidase Mia40. A ternary complex is formed between the substrate, Mia40 and the sulfhydryl oxidase Erv1, which is required for reoxidation of Mia40 (62)(63)(64). Although the small Tims contain no typical cleavable N-terminal signal sequence, a linear targeting signal within Tim9 and Tim10 has recently been shown to direct proteins across the outer membrane to the Mia40 translocase (65).…”

Section: Biogenesis Of Small Timsmentioning

confidence: 99%

Mitochondrial ATP‐independent chaperones

2009

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SummaryMitochondria possess a dedicated-chaperone system in the intermembrane space, the small Tims that are ubiquitous in all eukaryotes from yeast to man. They escort membrane proteins to the outer or the inner membrane for proper insertion. These mitochondrial chaperones do not require external energy to perform their function and have structural similarities to other ATP-independent chaperones. Here, we discuss their structural properties and how these relate to their chaperoning function in the mitochondrial intermembrane space.

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Erv1 Mediates the Mia40-dependent Protein Import Pathway and Provides a Functional Link to the Respiratory Chain by Shuttling Electrons to Cytochrome c

Cited by 208 publications

References 41 publications

Structural basis of yeast Tim40/Mia40 as an oxidative translocator in the mitochondrial intermembrane space

Structural basis of yeast Tim40/Mia40 as an oxidative translocator in the mitochondrial intermembrane space

Functional Characterization of Mia40p, the Central Component of the Disulfide Relay System of the Mitochondrial Intermembrane Space

Mitochondrial ATP‐independent chaperones

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