Allosteric regulation of BH3-in-groove interactions by tail anchors of BCL-xL complexes limits BH3 mimetic antagonism

Laurent Maillet (), Aurélie Fétiveau, Lisenn Lalier, Nena Martin, Sophie Barillé-Nion, Catherine Guette, Fabien Gautier, Stéphane Téletchéa and Philippe Paul Juin ()
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Laurent Maillet: Nantes Université, INSERM, CNRS, CRCI2NA, U1307, UMR6075
Aurélie Fétiveau: Nantes Université, INSERM, CNRS, CRCI2NA, U1307, UMR6075
Lisenn Lalier: Nantes Université, INSERM, CNRS, CRCI2NA, U1307, UMR6075
Nena Martin: Nantes Université, INSERM, CNRS, CRCI2NA, U1307, UMR6075
Sophie Barillé-Nion: Nantes Université, INSERM, CNRS, CRCI2NA, U1307, UMR6075
Catherine Guette: Nantes Université, INSERM, CNRS, CRCI2NA, U1307, UMR6075
Fabien Gautier: Nantes Université, INSERM, CNRS, CRCI2NA, U1307, UMR6075
Stéphane Téletchéa: Nantes Université, CNRS, US2B, UMR 6286
Philippe Paul Juin: Nantes Université, INSERM, CNRS, CRCI2NA, U1307, UMR6075

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract BCL-xL promotes cell survival by binding BH3-only initiators through its hydrophobic groove. Combining resonance energy transfer assays and molecular dynamics simulations, we unravel that membrane anchoring of BCL-xL via its tail anchor selectively advantages binding to membrane-anchored PUMA initiator over BH3 mimetic ligands of the groove. This is due to the combined allosteric effect on BH3-in-groove binding of BCL-xL and PUMA tail anchors. Moreover, doubly anchored PUMA / BCL-xL complexes recruit endogenous BAX, which favors their antagonism by BH3 mimetics. BAX’s tail anchor alone is sufficient to enhance BH3 mimetics-induced death in cells expressing PUMA / BCL-xL. Our work supports a model in which the survival function of BCL-xL is regulated by a complex interplay between its tail anchor and those of its interacting partners. This enables both resistance to pharmacological inhibitors and modulation by BAX, which functions as a crucial feedback disruptor of the BCL-xL network.

Date: 2025
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DOI: 10.1038/s41467-025-65509-1

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