NADH-bound AIF activates the mitochondrial CHCHD4/MIA40 chaperone by a substrate-mimicry mechanism

ABSTRACT: Mitochondrial metabolism requires chaperoned import of disulfide-stabilized proteins via CHCHD4/MIA40 and its enigmatic interaction with oxidoreductase Apoptosis-Inducing Factor (AIF). By crystallizing human CHCHD4’s AIF-interaction domain with an activated AIF dimer, we uncover how NADH allosterically configures AIF to anchor CHCHD4’s β-hairpin and histidine helix motifs to the inner mitochondrial membrane. The structure further reveals similarity between the AIF-interaction domain and recognition sequences of CHCHD4 substrates. NMR and X-ray scattering (SAXS) solution measurements, mutational analyses, and biochemistry show that the substrate-mimicking AIF-interaction domain shields CHCHD4’s redox-sensitive active site. Disrupting this shield critically activates CHCHD4 substrate affini

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PROVIDER: S-BIAD1515 | bioimages |

REPOSITORIES: bioimages