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.

Molecular recognition and substrate mimicry drive the electron-transfer process between MIA40 and ALR / L.Banci; I.Bertini; V.Calderone; C.Cefaro; S.Ciofi-Baffoni; A.Gallo; E.Kallergi; E.Lionaki; C.Pozidis; K.Tokatlidis. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - STAMPA. - 108 (12):(2011), pp. 4811-4816. [10.1073/pnas.1014542108]

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

BANCI, LUCIA;BERTINI, IVANO;CALDERONE, VITO;CEFARO, CHIARA;CIOFI BAFFONI, SIMONE;GALLO, ANGELO;
2011

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.
2011
108 (12)
4811
4816
L.Banci; I.Bertini; V.Calderone; C.Cefaro; S.Ciofi-Baffoni; A.Gallo; E.Kallergi; E.Lionaki; C.Pozidis; K.Tokatlidis
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/423880
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