Mia40, a novel factor for protein import into the intermembrane space of mitochondria is able to bind metal ions

Terziyska, Nadia; Lutz, Thomas; Kozany, C.; Mokranjac, Dejana; Mesecke, Nikola; Neupert, Walter; Herrmann, Johannes M.; Hell, Kai

doi:10.1016/j.febslet.2004.11.072

Cited by 154 publications

(172 citation statements)

References 22 publications

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“…To examine whether this modification influenced binding, we performed experiments in which the energy donor Trp was placed in Mia40 and the acceptor AEDANS in Cox17*. Four single-cysteine variants of Cox17* were produced and labelled with AEDANS (variants [8][9][10][11]. Their interaction with the wild-type form of Mia40 was then measured in equilibrium titrations, and its kinetics was followed in the stopped-flow instrument by the FRET between the single Trp (W294) of Mia40 and the AEDANS groups of the four Cox17* variants ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…T he intermembrane space (IMS) of the mitochondria was long believed to provide a reducing environment, similar to the cytosol, but recently proteins with disulphide bonds and subsequently a thiol oxidase (Mia40, mitochondrial import and assembly) were discovered in the IMS [1][2][3][4][5][6][7][8][9][10][11][12] . Unlike the other known thiol oxidases, Mia40 does not belong to the thioredoxin family, and its catalytic disulphide is arranged in a unique Cys-Pro-Cys motif.…”

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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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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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

Koch

Schmid

2014

Nat Commun

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“…For downregulation of Tim23, Tim50, and Mia40, published strains and procedures were used (Mokranjac et al, 2003a;Terziyska et al, 2005;.…”

Section: Plasmids Yeast Strains and Cell Growthmentioning

confidence: 99%

Role of Tim50 in the Transfer of Precursor Proteins from the Outer to the Inner Membrane of Mitochondria

Mokranjac

Sichting

Popov‐Čeleketić

et al. 2009

MBoC

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Transport of essentially all matrix and a number of inner membrane proteins is governed, entirely or in part, by N-terminal presequences and requires a coordinated action of the translocases of outer and inner mitochondrial membranes (TOM and TIM23 complexes). Here, we have analyzed Tim50, a subunit of the TIM23 complex that is implicated in transfer of precursors from TOM to TIM23. Tim50 is recruited to the TIM23 complex via Tim23 in an interaction that is essentially independent of the rest of the translocase. We find Tim50 in close proximity to the intermembrane space side of the TOM complex where it recognizes both types of TIM23 substrates, those that are to be transported into the matrix and those destined to the inner membrane, suggesting that Tim50 recognizes presequences. This function of Tim50 depends on its association with TIM23. We conclude that the efficient transfer of precursors between TOM and TIM23 complexes requires the concerted action of Tim50 with Tim23.

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“…Mia40p is present throughout the eukaryotic kingdom (12)(13)(14). In fungi, the large hydrophilic IMS domain of Mia40p is anchored to the inner membrane by an N-terminal transmembrane segment.…”

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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%

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

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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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Mia40, a novel factor for protein import into the intermembrane space of mitochondria is able to bind metal ions

Cited by 154 publications

References 22 publications

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

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

Role of Tim50 in the Transfer of Precursor Proteins from the Outer to the Inner Membrane of Mitochondria

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

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