Protein oxidative folding in the intermembrane mitochondrial space: More than protein trafficking
ABSTRACT The process of oxidative folding in the intermembrane mitochondrial space (IMS) is an exciting field of research because folding is simultaneously coupled to protein translocation and functional regulation. Contrary to the endoplasmatic reticulum ER where several chaperones of the disulfide isomerase family exist, oxidative folding in the IMS is exclusively catalyzed by the oxoreductase Mia40 that recognizes a group of proteins with characteristic cysteine motifs organized in twin CX(3)C, twin CX(9)C or CX(2)C motifs. In this review, we discuss the structural and biochemical studies leading to our current understanding of the Mia40 pathway as well as the open questions on the field. In fact, despite significant advances, several key points on the Mia40 pathway remain to clarify namely on the molecular mechanism trough which substrate oxidative folding is catalyzed. This issue is receiving increasing attention since failures in the import, sorting and folding of mitochondrial proteins is related to an increasing number of debilitating human disorders.
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- "Proteins that are secreted or trafficked through the mitochondrial intermembrane space are oxidized in the endoplasmic reticulum or mitochondrial intermembrane space, respectively (Fraga and Ventura, 2012; Hakim and Fass, 2010; Herrmann et al., 2009). The mitochondrial Erv (essential for respiration and viability) sulfhydryl oxidase is essential for mitochondrial biogenesis, respiratory chain function, and progression through the cell cycle. "
ABSTRACT: The Autographa californica M nucleopolyhedrovirus (AcMNPV) sulfhydryl oxidase Ac92 is essential for production of infectious virions. Ac92 also interacts with human p53 and enhances human p53-induced apoptosis in insect cells, but it is not known whether any relationship exists between Ac92 and native p53 homologs from insect hosts of AcMNPV. We found that Ac92 interacted with SfP53 from Spodoptera frugiperda in infected cells and oxidized SfP53 in vitro. However, Ac92 did not interact with or oxidize a mutant of SfP53 predicted to lack DNA binding. Silencing Sfp53 expression did not rescue the ability of an ac92-knockout virus to produce infectious virus. Similarly, ac92 expression did not affect SfP53-stimulated caspase activity or the localization of SfP53. Thus, although Ac92 binds to SfP53 during AcMNPV replication and oxidizes SfP53 in vitro, we could not detect any effects of this interaction on AcMNPV replication in cultured cells.Virology 12/2013; 447(1-2):197-207. DOI:10.1016/j.virol.2013.09.006 · 3.28 Impact Factor
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ABSTRACT: BACKGROUND: TIM15/Zim17 in yeast and its mammalian ortholog Hep are Zn(2+) finger (Cys4) proteins that assist mtHsp70 in protein import into the mitochondrial matrix. METHODS: Here we characterized the Zn(2+) induced TIM15 folding integrating biophysical and computational approaches. RESULTS: TIM15 folding occurs from an essentially unstructured conformation to a Zn(2+)-coordinated protein in a fast and markedly temperature-dependent process. Moreover, we demonstrate unambiguously that Zn(2+) induced TIM15 folding is essential for its role as mtHsp70 chaperone since in the unstructured apo state TIM15 does not bind to mtHsp70 and is unable to prevent its aggregation. Molecular dynamics simulations help to understand the crucial role of Zn(2+) in promoting a stable and functional 3D architecture in TIM15. It is shown that the metal ion, through its coordinating cysteine residues, can mediate relevant long-range effects with the interaction interface for mtHsp70 coupling thus folding and function. CONCLUSIONS: Zn(2+) induced TIM15 folding is essential for its function and likely occurs in mitochondrial matrix where high concentrations of Zn(2+) were reported. GENERAL SIGNIFICANCE: The combination of experimental and computational approaches presented here provide an integrated structural, kinetic and thermodynamic view of the folding of a mitochondrial zinc finger protein, which might be relevant to understand the organelle import of proteins sharing this fold.Biochimica et Biophysica Acta 01/2013; 1830(1):2139-49. DOI:10.1016/j.bbagen.2012.10.002 · 4.66 Impact Factor