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Structure. 2016 Dec 6;24(12):2067-2079. doi: 10.1016/j.str.2016.09.012. Epub 2016 Nov 3.

Defining NADH-Driven Allostery Regulating Apoptosis-Inducing Factor.

Author information

1
Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA; Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: cabrosey@mdanderson.org.
2
Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
MBIB Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
4
MBIB Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
5
Molecular Biology Consortium, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
6
MBIB Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: jtainer@mdanderson.org.

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.

KEYWORDS:

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

PMID:
27818101
PMCID:
PMC5143173
DOI:
10.1016/j.str.2016.09.012
[Indexed for MEDLINE]
Free PMC Article

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