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

Banci, L., Bertini, I., Calderone, V., Cefaro, C., Ciofi-Baffoni, S., Gallo, A., Kallergi, E., Lionaki, E., Pozidis, C. and Tokatlidis, K. (2011) Molecular recognition and substrate mimicry drive the electron-transfer process between MIA40 and ALR. Proceedings of the National Academy of Sciences of the United States of America, 108(12), pp. 4811-4816. (doi:10.1073/pnas.1014542108)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tokatlidis, Professor Kostas
Authors: Banci, L., Bertini, I., Calderone, V., Cefaro, C., Ciofi-Baffoni, S., Gallo, A., Kallergi, E., Lionaki, E., Pozidis, C., and Tokatlidis, K.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
ISSN (Online):1091-6490

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