Systematic Analysis of the Twin Cx9C Protein Family

Longen, Sebastian; Bien, Melanie; Bihlmaier, Karl; Kloeppel, Christine; Kauff, Frank; Hammermeister, Miriam; Westermann, Benedikt; Herrmann, Johannes M.; Riemer, Jan

doi:10.1016/j.jmb.2009.08.041

Cited by 162 publications

(188 citation statements)

References 50 publications

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“…Although previous studies have revealed a number of IMS proteins or protein domains that contain disulfide bond(s), which are likely transferred from Tim40, there are still many proteins or protein domains in the IMS that contain Cys residues whose formation of disulfide bonds remains to be experimentally confirmed (38,39). Here we find that the conserved Cys residues in Tim22 form an intramolecular disulfide bond.…”

mentioning

confidence: 50%

Intramolecular Disulfide Bond of Tim22 Protein Maintains Integrity of the TIM22 Complex in the Mitochondrial Inner Membrane

Okamoto

Miyagawa

Shiota

et al. 2014

Journal of Biological Chemistry

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Background: Tim22 is a central component of the mitochondrial inner membrane protein insertion machinery TIM22 complex. Results: Lack of the disulfide bond of Tim22 destabilizes Tim22 and impairs substrate protein assembly. Conclusion:The disulfide bond of Tim22 has a role in stabilization of the TIM22 complex, which is important for the TIM22 protein assembly pathway. Significance: Tim40(Mia40)/Erv1-independent disulfide bond formation contributes to protein stability in mitochondria.

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confidence: 50%

Intramolecular Disulfide Bond of Tim22 Protein Maintains Integrity of the TIM22 Complex in the Mitochondrial Inner Membrane

Okamoto

Miyagawa

Shiota

et al. 2014

Journal of Biological Chemistry

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“…Cys36 of Cox17 is the second cysteine of the twin CX 9 C motif. Interestingly, the three residues before and after this cysteine show a significantly higher hydrophobicity 28 than the residues surrounding the other cysteines in the mitochondrial CX 9 C proteins of yeast 29 (Supplementary Table S2). The second cysteine might thus be an initial target for Mia40 in several of these proteins.…”

Section: Discussionmentioning

confidence: 99%

“…This argues against a prominent role of this cysteine adjacent to the MISS/ITS motif. The sequence analysis of all CX 9 C proteins of yeast suggested that the residues in the MISS/ITS positions are hydrophobic, because they are used to pack the helix-helix interface and thus stabilize the folded conformation of these proteins 29 .…”

Section: Discussionmentioning

confidence: 99%

“…Sulphur atoms of the structural disulphides are coloured yellow, cysteines are numbered according to the amino-acid sequence. The first CX 9 C motif is coloured purple (residues [26][27][28][29][30][31][32][33], the second CX 9 C motif (residues 47-57) is magenta and the hydrophobic residues 37-39 following Cys36 are blue. The residues of the MISS/ITS sequence (F50, I51, Y54) and I37, L38, F39 are shown in ball and sticks representation.…”

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confidence: 99%

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Mia40 targets cysteines in a hydrophobic environment to direct oxidative protein folding in the mitochondria

Koch

Schmid

2014

Nat Commun

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Mia40 catalyses the oxidative folding of disulphide-containing proteins in the mitochondria. The folding pathway is directed by the formation of the first mixed disulphide between Mia40 and its substrate. Here, we employ Cox17 to elucidate the molecular determinants of this reaction. Mia40 engages initially in a dynamic non-covalent enzyme-substrate complex that forms and dissociates within milliseconds. Cys36 of Cox17 forms the mixed disulphide in an extremely rapid reaction that is limited by the preceding complex formation with Mia40. Cys36 reacts much faster than the three other cysteines of Cox17, because it neighbours three hydrophobic residues. Mia40 binds preferentially to hydrophobic regions and the dynamic nature of the non-covalent complex allows rapid reorientation for an optimal positioning of the reactive cysteine. Mia40 thus uses the unique proximity between its substrate-binding site and the catalytic disulphide to select a particular cysteine for forming the critical initial mixed disulphide.

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“…These proteins are located in the intermembrane space (IMS) of mitochondria. S. cerevisiae contains 14 members of this family, most of which are critical for the accumulation of normal amounts of cytochrome c oxidase and for growth on nonfermentable carbon sources (9,32). The cysteine residues in these proteins are required for their targeting to mitochondria; during the import reaction, these proteins interact with the oxidoreductase Mia40 in the IMS, which converts the reduced thiols in the imported precursor into oxidized disulfides that are found in the mature forms of these proteins (3,10,36,41).…”

Section: Innovationmentioning

confidence: 99%

Inaccurately Assembled CytochromecOxidase Can Lead to Oxidative Stress-Induced Growth Arrest

Bode

Longen

Morgan

et al. 2013

Antioxidants & Redox Signaling

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Aims: To identify yeast mutants that show a strong redox dependence of the ability to respire, we systematically screened a yeast deletion library for mutants that require the presence of reductants for growth on nonfermentable carbon sources. Results: Respirative growth of 44 yeast mutants was significantly improved by the addition of dithiothreitol or glutathione. Two mutants that were strongly stimulated by reductants lacked the proteins Cmc1 and Coa4. Both proteins belong to the family of ''twin Cx 9 C'' proteins present in the intermembrane space of mitochondria. Deletion of CMC1 or COA4 leads to assembly defects of cytochrome c oxidase, in particular to the lack of Cox1 and rapid degradation of Cox2 and Cox3. Interestingly, the presence of the reductants does not suppress these assembly defects and the levels of cytochrome c oxidase remain reduced. Reductants and antioxidants such as ascorbic acid rather counteract the effects of hydrogen peroxide that is produced from partially assembled cytochrome c oxidase intermediates. Innovation: Here we show that oxidative stress generated by the accumulation of partially assembled respiratory chain complexes prevents growth on carbon sources that force cells to respire. Conclusion: Defects in the assembly of cytochrome c oxidase can lead to increased production of hydrogen peroxide, which is sensed in cells and blocks their proliferation. We propose that this redox-regulated feedback regulation specifically slows down the propagation of cells carrying respiratory chain mutations in order to select for cells of high mitochondrial fitness. Antioxid. Redox Signal. 18, 1597-1612.

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Systematic Analysis of the Twin Cx9C Protein Family

Cited by 162 publications

References 50 publications

Intramolecular Disulfide Bond of Tim22 Protein Maintains Integrity of the TIM22 Complex in the Mitochondrial Inner Membrane

Intramolecular Disulfide Bond of Tim22 Protein Maintains Integrity of the TIM22 Complex in the Mitochondrial Inner Membrane

Mia40 targets cysteines in a hydrophobic environment to direct oxidative protein folding in the mitochondria

Inaccurately Assembled CytochromecOxidase Can Lead to Oxidative Stress-Induced Growth Arrest

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