Cysteine residues in mitochondrial intermembrane space proteins: more than just import

Habich, Markus; Salscheider, Silja Lucia; Riemer, Jan

doi:10.1111/bph.14480

Cited by 39 publications

(45 citation statements)

References 149 publications

(203 reference statements)

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“…Proteins of the mitochondrial intermembrane space (IMS) fulfill numerous critical functions, including enzymatic functions in metabolic pathways such as pyrimidine, lipid and heme biosynthesis, functions in the maintenance of mitochondrial morphology and dynamics, in assembly of the respiratory chain, and in maintenance of the mitochondrial proteome [ 1 – 5 ]. All IMS proteins are nuclear encoded and synthesized at cytosolic ribosomes.…”

Section: Introductionmentioning

confidence: 99%

The C-terminal region of the oxidoreductase MIA40 stabilizes its cytosolic precursor during mitochondrial import

et al. 2020

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Background The mitochondrial intermembrane space (IMS) is home to proteins fulfilling numerous essential cellular processes, particularly in metabolism and mitochondrial function. All IMS proteins are nuclear encoded and synthesized in the cytosol and must therefore be correctly targeted and transported to the IMS, either through mitochondrial targeting sequences or conserved cysteines and the mitochondrial disulfide relay system. The mitochondrial oxidoreductase MIA40, which catalyzes disulfide formation in the IMS, is imported by the combined action of the protein AIFM1 and MIA40 itself. Here, we characterized the function of the conserved highly negatively charged C-terminal region of human MIA40. Results We demonstrate that the C-terminal region is critical during posttranslational mitochondrial import of MIA40, but is dispensable for MIA40 redox function in vitro and in intact cells. The C-terminal negatively charged region of MIA40 slowed import into mitochondria, which occurred with a half-time as slow as 90 min. During this time, the MIA40 precursor persisted in the cytosol in an unfolded state, and the C-terminal negatively charged region served in protecting MIA40 from proteasomal degradation. This stabilizing property of the MIA40 C-terminal region could also be conferred to a different mitochondrial precursor protein, COX19. Conclusions Our data suggest that the MIA40 precursor contains the stabilizing information to allow for postranslational import of sufficient amounts of MIA40 for full functionality of the essential disulfide relay. We thereby provide for the first time mechanistic insights into the determinants controlling cytosolic surveillance of IMS precursor proteins.

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Section: Introductionmentioning

confidence: 99%

The C-terminal region of the oxidoreductase MIA40 stabilizes its cytosolic precursor during mitochondrial import

et al. 2020

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“…It is well known that many proteins in the intermembrane space (IMS) contain conserved cysteine-rich sections [40]. There is still no explanation for the function of these tracts [40]. It should be noted that according to our previous results, the second most susceptible AA is cysteine [10].…”

Section: Discussionmentioning

confidence: 59%

“…For example, the proteins of the respiratory chain are embedded in membranes while one side is in contact with a more aggressive environment [39]. It is well known that many proteins in the intermembrane space (IMS) contain conserved cysteine-rich sections [40]. There is still no explanation for the function of these tracts [40].…”

Section: Discussionmentioning

confidence: 99%

Influence of spatial structure on protein damage susceptibility – A bioinformatics approach

Fichtner

Schuster

Stark

2020

Preprint

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Aging research is a very popular field of research in which the gradual transformation of functional states into dysfunctional states are studied. Here we only consider the molecular level, which can also have effects on the macroscopic level. It is known that the proteinogenic amino acids differ in their modification susceptibilities and this can affect the function of proteins. For this it is important to know the distribution of amino acids between the protein surface/shell and the core. This was investigated in this study for all known structural data of peptides and proteins. As a result it is shown that the surface contains less susceptible amino acids than the core with the exception of thermophilic organisms. Furthermore, proteins could be classified according to their susceptibility. This can then be used in applications such as phylogeny, aging research, molecular medicine and synthetic biology. KeywordsAmino acid score, 3-dimensional protein structure, protein shell, protein core, protein damage, protein aging, concave hull

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“…Classical substrates of this pathway are small proteins that share characteristic folds and cysteine patterns. Recently, several non‐conventional substrates were identified that do not fit these features demonstrating that the disulfide relay possesses a high degree of substrate versatility (Habich et al , ).…”

Section: The Proteasome Controls Disulfide Relay‐mediated Protein Impmentioning

confidence: 99%

Stop wasting protein—Proteasome inhibition to target diseases linked to mitochondrial import

Habich

Riemer

2019

EMBO Mol Med

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Mitochondrial dysfunction is linked to various human diseases. Symptoms can occur early in life or manifest progressively during life and include poor muscle coordination or weakness, neurological or developmental problems, or immunodeficiency (Lightowlers et al , 2015). Most mitochondrial diseases are caused by mutations in genes encoding mitochondrial proteins. Mutations can affect protein functions in many ways; they can not only impair enzymatic activities, but also lower protein stability, hamper assembly into multimeric protein complexes, or abrogate protein transport into mitochondria. Understanding the impact of mutations on protein function is crucial to understand pathophysiological mechanisms of mitochondrial diseases and to develop therapeutic approaches.

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Cysteine residues in mitochondrial intermembrane space proteins: more than just import

Cited by 39 publications

References 149 publications

The C-terminal region of the oxidoreductase MIA40 stabilizes its cytosolic precursor during mitochondrial import

The C-terminal region of the oxidoreductase MIA40 stabilizes its cytosolic precursor during mitochondrial import

Influence of spatial structure on protein damage susceptibility – A bioinformatics approach

Stop wasting protein—Proteasome inhibition to target diseases linked to mitochondrial import

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