A redox switch regulates the structure and function of anti-apoptotic BFL-1
In: Nature Structural and Molecular Biology, Jg. 27 (2020-09-02), Heft 9, S. 781-789
serialPeriodical
Zugriff:
Apoptosis is regulated by BCL-2 family proteins. Anti-apoptotic members suppress cell death by deploying a surface groove to capture the critical BH3 α-helix of pro-apoptotic members. Cancer cells hijack this mechanism by overexpressing anti-apoptotic BCL-2 family proteins to enforce cellular immortality. We previously identified and harnessed a unique cysteine (C55) in the groove of anti-apoptotic BFL-1 to selectively neutralize its oncogenic activity using a covalent stapled-peptide inhibitor. Here, we find that disulfide bonding between a native cysteine pair at the groove (C55) and C-terminal α9 helix (C175) of BFL-1 operates as a redox switch to control the accessibility of the anti-apoptotic pocket. Reducing the C55–C175 disulfide triggers α9 release, which promotes mitochondrial translocation, groove exposure for BH3 interaction and inhibition of mitochondrial permeabilization by pro-apoptotic BAX. C55–C175 disulfide formation in an oxidative cellular environment abrogates the ability of BFL-1 to bind BH3 domains. Thus, we identify a mechanism of conformational control of BFL-1 by an intramolecular redox switch.
Titel: |
A redox switch regulates the structure and function of anti-apoptotic BFL-1
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Autor/in / Beteiligte Person: | Korshavn, Kyle J. ; Wales, Thomas E. ; Bird, Gregory H. ; Engen, John R. ; Walensky, Loren D. |
Zeitschrift: | Nature Structural and Molecular Biology, Jg. 27 (2020-09-02), Heft 9, S. 781-789 |
Veröffentlichung: | 2020 |
Medientyp: | serialPeriodical |
ISSN: | 1545-9993 (print) ; 1545-9985 (print) |
DOI: | 10.1038/s41594-020-0458-9 |
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