4BV6

Refined crystal structure of the human Apoptosis inducing factor

Summary for 4BV6

• Entry DOI: 10.2210/pdb4bv6/pdb
• Related: 4BUR
• Descriptor: APOPTOSIS-INDUCING FACTOR 1, MITOCHONDRIAL, FLAVIN-ADENINE DINUCLEOTIDE, GLYCEROL, ... (4 entities in total)
• Functional Keywords: oxidoreductase, apoptosis, nuclear chromatinolysis, dna binding
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Mitochondrion intermembrane space. Isoform 3: Mitochondrion intermembrane space. Isoform 5: Cytoplasm: O95831
• Total number of polymer chains: 1
• Total formula weight: 54821.90

Authors

Martinez-Julvez, M.,Herguedas, B.,Hermoso, J.A.,Ferreira, P.,Villanueva, R.,Medina, M. (deposition date: 2013-06-25, release date: 2014-09-17, Last modification date: 2024-05-08)

Primary citation

Ferreira, P.,Villanueva, R.,Martinez-Julvez, M.,Herguedas, B.,Marcuello, C.,Fernandez-Silva, P.,Cabon, L.,Hermoso, J.A.,Lostao, A.,Susin, S.A.,Medina, M.
Structural Insights Into the Coenzyme Mediated Monomer-Dimer Transition of the Pro-Apoptotic Apoptosis Inducing Factor.
Biochemistry, 53:4204-, 2014

PubMed Abstract: The 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.

PubMed: 24914854
DOI: 10.1021/BI500343R

Experimental method

X-RAY DIFFRACTION (1.8 Å)