Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 12, Pages 4811-4816Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1014542108
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Funding
- European Union [228461]
- IMBB-FORTH
- University of Crete
- European Social Fund
- National Grid Initiatives of Italy and Germany [213010]
- Italian Ministero dell'Istruzione, dell'Universita e della Ricerca-Fondo per gli Investimenti della Ricerca di Base [PROTEOMICA-RBRN07BMCT]
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Oxidative protein folding in the mitochondrial intermembrane space requires the transfer of a disulfide bond from MIA40 to the substrate. During this process MIA40 is reduced and regenerated to a functional state through the interaction with the flavin-dependent sulfhydryl oxidase ALR. Here we present the mechanistic basis of ALR-MIA40 interaction at atomic resolution by biochemical and structural analyses of the mitochondrial ALR isoform and its covalent mixed disulfide intermediate with MIA40. This ALR isoform contains a folded FAD-binding domain at the C-terminus and an unstructured, flexible N-terminal domain, weakly and transiently interacting one with the other. A specific region of the N-terminal domain guides the interaction with the MIA40 substrate binding cleft (mimicking the interaction of the substrate itself), without being involved in the import of ALR. The hydrophobicity-driven binding of this region ensures precise protein-protein recognition needed for an efficient electron transfer process.
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