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Title: Defining NADH-Driven Allostery Regulating Apoptosis-Inducing Factor

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. In this paper, 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. Finally, 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.
Authors:
 [1] ;  [2] ;  [2] ;  [2] ;  [3] ;  [4] ;  [5] ;  [2] ;  [2] ;  [6]
  1. Washington Univ. School of Medicine, St. Louis, MO (United States). Biochemistry and Molecular Biophysics; Univ. of Texas M.D. Anderson Cancer Center, Houston, TX (United States). Molecular and Cellular Oncology
  2. Washington Univ. School of Medicine, St. Louis, MO (United States). Biochemistry and Molecular Biophysics
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). MBIB Division
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). MBIB Division; Univ. of California, Santa Cruz, CA (United States). Chemistry and Biochemistry
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biology Consortium
  6. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). MBIB Division; Univ. of Texas M.D. Anderson Cancer Center, Houston, TX (United States). Molecular and Cellular Oncology
Publication Date:
Grant/Contract Number:
AC02-05CH11231; P01 CA92584; F32-GM109591
Type:
Published Article
Journal Name:
Structure
Additional Journal Information:
Journal Volume: 24; Journal Issue: 12; Journal ID: ISSN 0969-2126
Publisher:
Elsevier
Research Org:
Washington Univ., St. Louis, MO (United States). School of Medicine; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of Texas M.D. Anderson Cancer Center, Houston, TX (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Inst. of Health (NIH) (United States); Washington Univ. School of Medicine (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; apoptosis-inducing factor; charge-transfer complex; flavoswitch; parthanatos; mitochondrial homeostasis; allostery; SAXS; X-ray crystallography; molecular dynamics
OSTI Identifier:
1460434
Alternate Identifier(s):
OSTI ID: 1411645