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Structural insights into the coenzyme mediated monomer-dimer transition of the pro-apoptotic apoptosis inducing factor

AutorFerreira, Patricia ; Villanueva, Raquel; Martínez-Júlvez, Marta; Herguedas, Beatriz.; Marcuello, C.; Fernández-Silva, Patricio; Cabon, L.; Hermoso, Juan A. ; Lostao, Anabel; Susín, Santos Antonio; Medina, Milagros
Fecha de publicación2014
EditorAmerican Chemical Society
CitaciónBiochemistry 53: 4204- 4215 (2014)
ResumenThe apoptosis-inducing factor (AIF) is a mitochondrial-flavoprotein that, after cell death induction, is distributed to the nucleus to mediate chromatinolysis. In mitochondria, AIF is present in a monomer-dimer equilibrium that after reduction by NADH gets displaced toward the dimer. The crystal structure of the human AIF (hAIF):NAD(H)-bound dimer revealed one FAD and, unexpectedly, two NAD(H) molecules per protomer. A 1:2 hAIF:NAD(H) binding stoichiometry was additionally confirmed in solution by using surface plasmon resonance. The here newly discovered NAD(H)-binding site includes residues mutated in human disorders, and accommodation of the coenzyme in it requires restructuring of a hAIF portion within the 509-560 apoptogenic segment. Disruption of interactions at the dimerization surface by production of the hAIF E413A/R422A/R430A mutant resulted in a nondimerizable variant considerably less efficiently stabilizing charge-transfer complexes upon coenzyme reduction than WT hAIF. These data reveal that the coenzyme-mediated monomer-dimer transition of hAIF modulates the conformation of its C-terminal proapoptotic domain, as well as its mechanism as reductase. These observations suggest that both the mitochondrial and apoptotic functions of hAIF are interconnected and coenzyme controlled: a key information in the understanding of the physiological role of AIF in the cellular life and death cycle. © 2014 American Chemical Society.
URIhttp://hdl.handle.net/10261/167838
Identificadoresdoi: 10.1021/bi500343r
issn: 1520-4995
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