Protein Oxidative Folding in the Intermembrane Mitochondrial Space: More than Protein Trafficking

Departament de Bioquímica i Biologia Molecular, Facultat de Ciències, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
Current Protein and Peptide Science (Impact Factor: 3.15). 05/2012; 13(3):224-31. DOI: 10.2174/138920312800785012
Source: PubMed


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. "
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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.
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