title: Zinc can play chaperone-like and inhibitor roles during import of mitochondrial small Tim proteins.
abstract: Zinc is an essential cofactor required for the function of approximately 8% of the yeast and 10% of the human proteome. All of the "small Tim" proteins of the mitochondrial intermembrane space contain a strictly conserved "twin CX(3)C" zinc finger motif, which can bind zinc ions in the Cys-reduced form. We have shown previously that although disulfide bond formation is essential for the function of these proteins in mitochondria, only reduced proteins can be imported into mitochondria (Lu, H., Allen, S., Wardleworth, L., Savory, P., and Tokatlidis, K. (2004) J. Biol. Chem. 279, 18952-18958 and Morgan, B., and Lu, H. (2008) Biochem. J. 411, 115-122). However, the role of zinc during the import of these proteins is unclear. This study shows that the function of zinc is complex. It can play a thiol stabilizer role preventing oxidative folding of the small Tim proteins and maintaining the proteins in an import-competent form. On the other hand, zinc-bound forms cannot be imported into mitochondria efficiently. Furthermore, our results show that zinc is a powerful inhibitor of Erv1, an essential component of the import pathway used by the small Tim proteins. We propose that zinc plays a chaperone-like role in the cytosol during biogenesis of the small Tim proteins and that the proteins are imported into mitochondria through the apo-forms.
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom.
authors.forename: Bruce
authors.initials: B
authors.lastname: Morgan
authors.forename: Swee Kim
authors.initials: SK
authors.lastname: Ang
authors.forename: Guanhua
authors.initials: G
authors.lastname: Yan
authors.forename: Hui
authors.initials: H
authors.lastname: Lu
mesh_terms: D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D050862:Oxidoreductases Acting on Sulfur Group Donors; D017510:Protein Folding; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins; C107250:TIM10 protein, S cerevisiae; C116366:Tim9 protein, S cerevisiae; D050862:Oxidoreductases Acting on Sulfur Group Donors; C073790:ERV1 protein, S cerevisiae; D015032:Zinc