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Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4811-6. doi: 10.1073/pnas.1014542108. Epub 2011 Mar 7.

Molecular recognition and substrate mimicry drive the electron-transfer process between MIA40 and ALR.

Author information

1
Magnetic Resonance Center (CERM), University of Florence, Via Luigi Sacconi 6, Sesto Fiorentino, 50019 Florence, Italy. banci@cerm.unifi.it

Abstract

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.

PMID:
21383138
PMCID:
PMC3064372
DOI:
10.1073/pnas.1014542108
[Indexed for MEDLINE]
Free PMC Article

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