Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 47, Pages 20190-20195Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1010095107
Keywords
NMR; oxidative protein folding; protein folding intermediates
Categories
Funding
- SPINE-II-COMPLEXES [LSHG-CT-2006-031220]
- EU-NMR [026145]
- Italian MIUR-FIRB [PROTEOMICA-RBRN-07BMCT]
- IMBB-FORTH
- University of Crete
- European Social Fund and National Resources
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Several proteins of the mitochondrial intermembrane space are targeted by internal targeting signals. A class of such proteins with alpha-helical hairpin structure bridged by two intramolecular disulfides is trapped by a Mia40-dependent oxidative process. Here, we describe the oxidative folding mechanism underpinning this process by an exhaustive structural characterization of the protein in all stages and as a complex with Mia40. Two consecutive induced folding steps are at the basis of the protein-trapping process. In the first one, Mia40 functions as a molecular chaperone assisting alpha-helical folding of the internal targeting signal of the substrate. Subsequently, in a Mia40-independent manner, folding of the second substrate helix is induced by the folded targeting signal functioning as a folding scaffold. The Mia40-induced folding pathway provides a proof of principle for the general concept that internal targeting signals may operate as a folding nucleus upon compartment-specific activation.
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