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Redox and ligand binding dependent conformational ensembles in the human apoptosis-inducing factor regulate its pro-life and cell death functions.

AIMS: The Human apoptosis-inducingfactor (hAIF) supports OXPHOS biogenesis and programmed cell death, with missense mutations producing neurodegenerative phenotypes. hAIF senses the redox environment of cellular compartments, stabilizing a charge-transfer complex (CTC) dimer that modulates the protein interaction network. In this context we aimed to evaluate the subcellular pH, CTC formation, and pathogenic mutations effects on hAIF stability, and a thermal denaturation high-throughput screening (HTS) assay to discover AIF binders.

RESULTS: Apoptotic hAIF∆1-101 is not stable at intermembrane space (IMS) pH, but the 77-101 residues confer stability to the mitochondrial isoform. hAIF and its CTC populate different conformational ensembles with redox switch to the CTC producing a less stable and compact protein. The pathogenic G308E, R201 and E493V mutations modulate hAIF stability; particularly, R201 causes a population shift to a less stable conformation that remodels the active site structure and dynamics. We have identified new molecules that modulate the hAIF NADH/NAD+ association/dissociation equilibrium and regulate its catalytic efficiency.

INNOVATION: Biophysical methods allow evaluating the regulation of hAIF functional ensembles and to develop an HTS assay to discover small molecules that might modulate hAIF stability and activities.

CONCLUSION: The mitochondrial soluble 54-77 portion stabilizes hAIF at the IMS pH. NADH-redox linked conformational changes course with strong NAD+ binding and protein dimerization, but they produce a negative impact in overall hAIF stability. Loss of functionality in the R201 deletion is due to distortion of the active site architecture. We report molecules that may serve as leads in the development of hAIF bioactive compound.

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