Characterization of an alternative BAK-binding site for BH3 peptides.
Adaptor Proteins, Signal Transducing
/ chemistry
Amino Acid Sequence
Animals
Apoptosis Regulatory Proteins
/ chemistry
Binding Sites
/ genetics
Cells, Cultured
Humans
Jurkat Cells
Magnetic Resonance Spectroscopy
Mice, Knockout
Mitochondrial Membranes
/ metabolism
Molecular Dynamics Simulation
Mutation
Protein Binding
Protein Domains
Proto-Oncogene Proteins c-bcl-2
/ chemistry
Sequence Homology, Amino Acid
bcl-2 Homologous Antagonist-Killer Protein
/ chemistry
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
03 07 2020
03 07 2020
Historique:
received:
03
06
2019
accepted:
05
06
2020
entrez:
5
7
2020
pubmed:
6
7
2020
medline:
1
9
2020
Statut:
epublish
Résumé
Many cellular stresses are transduced into apoptotic signals through modification or up-regulation of the BH3-only subfamily of BCL2 proteins. Through direct or indirect mechanisms, these proteins activate BAK and BAX to permeabilize the mitochondrial outer membrane. While the BH3-only proteins BIM, PUMA, and tBID have been confirmed to directly activate BAK through its canonical BH3 binding groove, whether the BH3-only proteins BMF, HRK or BIK can directly activate BAK is less clear. Here we show that BMF and HRK bind and directly activate BAK. Through NMR studies, site-directed mutagenesis, and advanced molecular dynamics simulations, we also find that BAK activation by BMF and possibly HRK involves a previously unrecognized binding groove formed by BAK α4, α6, and α7 helices. Alterations in this groove decrease the ability of BMF and HRK to bind BAK, permeabilize membranes and induce apoptosis, suggesting a potential role for this BH3-binding site in BAK activation.
Identifiants
pubmed: 32620849
doi: 10.1038/s41467-020-17074-y
pii: 10.1038/s41467-020-17074-y
pmc: PMC7335050
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Apoptosis Regulatory Proteins
0
BCL2 protein, human
0
BMF protein, human
0
HRK protein, human
0
Proto-Oncogene Proteins c-bcl-2
0
bcl-2 Homologous Antagonist-Killer Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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