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Leitl, K. ; Sperl, L.E.* ; Hagn, F.

Preferred inhibition of pro-apoptotic Bak by BclxL via a two-step mechanism.

Cell Rep. 43:114526 (2024)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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
Sprache englisch
Veröffentlichungsjahr 2024
HGF-Berichtsjahr 2024
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Zeitschrift Cell Reports
Quellenangaben Band: 43, Heft: 8, Seiten: , Artikelnummer: 114526 Supplement: ,
Verlag Cell Press
Verlagsort 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503094-001
G-503000-001
Förderungen DFG
DOI 10.1016/j.celrep.2024.114526
WOS ID 001278575600001
Scopus ID 85199168884
PubMed ID 39046879
Erfassungsdatum 2024-07-30
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