5KVI

Crystal structure of monomeric human apoptosis-inducing factor with E413A/R422A/R430A mutations

Summary for 5KVI

• Entry DOI: 10.2210/pdb5kvi/pdb
• Descriptor: Apoptosis-inducing factor 1, mitochondrial, FLAVIN-ADENINE DINUCLEOTIDE, 4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID, ... (5 entities in total)
• Functional Keywords: oxidoreductase, flavoprotein, mitochondria cell death
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 60356.25

Authors

Brosey, C.A.,Nix, J.,Ellenberger, T.,Tainer, J.A. (deposition date: 2016-07-14, release date: 2016-11-16, Last modification date: 2023-10-04)

Primary citation

Brosey, C.A.,Ho, C.,Long, W.Z.,Singh, S.,Burnett, K.,Hura, G.L.,Nix, J.C.,Bowman, G.R.,Ellenberger, T.,Tainer, J.A.
Defining NADH-Driven Allostery Regulating Apoptosis-Inducing Factor.
Structure, 24:2067-2079, 2016

PubMed 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.

PubMed: 27818101
DOI: 10.1016/j.str.2016.09.012

Experimental method

X-RAY DIFFRACTION (1.995 Å)