Defining NADH-Driven Allostery Regulating Apoptosis-Inducing Factor

Chris A. Brosey, Chris Ho, Winnie Z. Long, Sukrit Singh, Kathryn Burnett, Greg L. Hura, Jay C. Nix, Gregory R. Bowman, Tom Ellenberger, John A. Tainer

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Apoptosis-inducing factor (AIF) is critical for mitochondrial respiratory complex biogenesis and for mediating necroptotic parthanatos; these functions are seemingly regulated by enigmatic allosteric switching driven by NADH charge-transfer complex (CTC) formation. Here, we define molecular pathways linking AIF's active site to allosteric switching regions by characterizing dimer-permissive mutants using small-angle X-ray scattering (SAXS) and crystallography and by probing AIF-CTC communication networks using molecular dynamics simulations. Collective results identify two pathways propagating allostery from the CTC active site: (1) active-site H454 links to S480 of AIF's central β-strand to modulate a hydrophobic border at the dimerization interface, and (2) an interaction network links AIF's FAD cofactor, central β-strand, and Cβ-clasp whereby R529 reorientation initiates C-loop release during CTC formation. This knowledge of AIF allostery and its flavoswitch mechanism provides a foundation for biologically understanding and biomedically controlling its participation in mitochondrial homeostasis and cell death.

Original languageEnglish
Pages (from-to)2067-2079
Number of pages13
JournalStructure
Volume24
Issue number12
DOIs
StatePublished - Dec 6 2016

Keywords

  • SAXS
  • X-ray crystallography
  • allostery
  • apoptosis-inducing factor
  • charge-transfer complex
  • flavoswitch
  • mitochondrial homeostasis
  • molecular dynamics
  • parthanatos

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