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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)
Publ. Version/Full Text DOI PMC
Open Access Gold
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords 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
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 2211-1247
e-ISSN 2211-1247
Journal Cell Reports
Quellenangaben Volume: 43, Issue: 8, Pages: , Article Number: 114526 Supplement: ,
Publisher Cell Press
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Structural Biology (STB)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-503094-001
G-503000-001
Grants 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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