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BAX Activation: Mutations Near Its Proposed Non-canonical BH3 Binding Site Reveal Allosteric Changes Controlling Mitochondrial Association.
- Source :
-
Cell reports [Cell Rep] 2019 Apr 09; Vol. 27 (2), pp. 359-373.e6. - Publication Year :
- 2019
-
Abstract
- To elicit apoptosis, BAX metamorphoses from an inert cytosolic monomer into homo-oligomers that permeabilize the mitochondrial outer membrane (MOM). A long-standing puzzle is that BH3 domains apparently activate BAX by not only its canonical groove but also a proposed site involving helices α1 and α6. Our mutagenesis studies reveal that late steps like oligomerization require activation through the groove but probably not earlier steps like MOM association. Conversely, α1 or α6 obstruction and alanine mutagenesis scanning implicate these helices early in BAX activation. The α1 and α6 mutations lowered BH3 binding, altered the BAX conformation, and reduced its MOM translocation and integration; their exposure of the BAX α1-α2 loop allosterically sequestered its α9 membrane anchor in the groove. The crystal structure of an α6 mutant revealed additional allosteric effects. The results suggest that the α1 and α6 region drives MOM association and integration, whereas groove binding favors subsequent steps toward oligomerization.<br /> (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Amino Acid Sequence
Animals
Binding Sites
Female
Humans
Male
Mice
Mice, Inbred C57BL
Models, Molecular
Peptide Fragments metabolism
Proto-Oncogene Proteins metabolism
Sequence Alignment
Mitochondria, Liver metabolism
Mitochondrial Membranes metabolism
Mutation
bcl-2-Associated X Protein genetics
bcl-2-Associated X Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 27
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 30970242
- Full Text :
- https://doi.org/10.1016/j.celrep.2019.03.040