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

Patricia Ferreira1, Raquel Villanueva, Marta Martínez-Júlvez

  • 1Departamento de Bioquímica y Biología Molecular y Celular, ‡Instituto de Biocomputación y Física de Sistemas Complejos (BIFI)-Joint Unit BIFI-IQFR (CSIC), and §Laboratorio de Microscopias Avanzadas, Instituto de Nanociencia de Aragón (INA), Universidad de Zaragoza , Zaragoza, Spain.

Biochemistry
|June 11, 2014
PubMed

Insights

The apoptosis-inducing factor (AIF) is regulated by coenzyme binding, influencing its mitochondrial and apoptotic functions. This discovery deepens our understanding of cellular life and death cycles.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • The apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein crucial for inducing cell death.
  • AIF translocates to the nucleus to mediate chromatinolysis upon cell death induction.
  • In mitochondria, AIF exists in a monomer-dimer equilibrium influenced by NADH.

Purpose of the Study:

  • To elucidate the structural and functional roles of NAD(H) binding to human AIF (hAIF).
  • To investigate how coenzyme binding affects hAIF's monomer-dimer transition and apoptotic activity.

Main Methods:

  • Crystal structure determination of hAIF bound to NAD(H).
  • Surface plasmon resonance (SPR) to confirm hAIF:NAD(H) stoichiometry in solution.
  • Site-directed mutagenesis to study the role of dimerization surface residues.

Main Results:

  • The crystal structure revealed an unexpected 1:2 hAIF:NAD(H) binding stoichiometry per protomer.
  • A novel NAD(H)-binding site was identified, including residues linked to human disorders.
  • Disruption of dimerization via mutagenesis reduced the efficiency of charge-transfer complex stabilization.
  • Coenzyme binding induces conformational changes in the apoptogenic C-terminal domain.

Conclusions:

  • Coenzyme binding to hAIF modulates its monomer-dimer transition and reductase activity.
  • The mitochondrial and apoptotic functions of hAIF are interconnected and controlled by coenzymes.
  • This provides key insights into the physiological role of AIF in cellular life and death.

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