Allosteric regulation of BH3-in-groove interactions by tail anchors of BCL-xL complexes limits BH3 mimetic antagonism
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.
Authors
- Philippe Juin (ORCID: https://orcid.org/0000-0002-4997-3888)
- Aurélie Fétiveau
- Stéphane Téletchéa (ORCID: https://orcid.org/0000-0002-2402-028X)
- Catherine Guette (ORCID: https://orcid.org/0000-0003-1779-9931)
- Sophie Barillé‐Nion (ORCID: https://orcid.org/0000-0001-5171-9937)
- Fabien Gautier
- Nadine Martin (ORCID: https://orcid.org/0000-0002-4806-2388)
- Laurent Maillet (ORCID: https://orcid.org/0000-0002-8169-060X)
- Lisenn Lalier-Bretaudeau (ORCID: https://orcid.org/0000-0001-5400-9527)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers (FR)
- La Ligue Contre le Cancer (FR)
- Institut de Cancérologie de l'Ouest (FR)
- Unité en Sciences Biologiques et Biotechnologies de Nantes (FR)
- Nantes Université (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-22
- DOI
- https://doi.org/10.1038/s41467-025-65509-1
- Citations
- 1
- Primary Topic
- Microtubule and mitosis dynamics
- Type
- article
- Field-Weighted Citation Impact
- 1.15
Funders
- Infrastructures en Biologie Santé et Agronomie
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Ligue Contre le Cancer
- Centre National de la Recherche Scientifique
- Institut National Du Cancer
- Direction Générale de l’offre de Soins