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Preferred inhibition of pro-apoptotic Bak by BclxL via a two-step mechanism.
Cell Rep. 43:114526 (2024)
Bak is a pore-forming Bcl2 protein that induces apoptosis at the outer mitochondrial membrane, which can either proceed via Bak oligomerization or be inhibited by anti-apoptotic Bcl2 proteins, such as BclxL. BclxL is very efficient in inhibiting Bak pore formation, but the mechanistic basis of this preferred interaction has remained enigmatic. Here, we identify Bakα1 as a second binding site for BclxL and show that it specifically interacts with the Bcl2-homology (BH)3 binding groove of BclxL. The affinity between BclxL and Bakα1 is weaker than with Bak-BH3, suggesting that Bakα1, being exposed early in the pore-forming trajectory, transiently captures BclxL, which subsequently transitions to the proximal BH3 site. Bak variants where the initial transient interaction with BclxL is modulated show a markedly altered response to BclxL inhibition. This work contributes to a better mechanistic understanding of the fine-tuned interactions between different players of the Bcl2 protein family.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Cp: Cell Biology ; Cp: Molecular Biology ; Hdx-ms ; Nmr ; Apoptosis ; Inhibition ; Lipid Nanodiscs ; Membrane; Conformational-changes; Bh3 Domains; Proteins; Binding; Activation; Membranes; Oligomerization; Interface; Release; Ligand
ISSN (print) / ISBN
2211-1247
e-ISSN
2211-1247
Zeitschrift
Cell Reports
Quellenangaben
Band: 43,
Heft: 8,
Artikelnummer: 114526
Verlag
Cell Press
Verlagsort
50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Structural Biology (STB)
Förderungen
DFG