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

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 C-terminal tail 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 C-terminal sequence alone is suffi-cient 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 inter-play 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Colon Epithelial Cell, Colon

DISEASE(S): Colon Cancer

SUBMITTER: François Guillonneau  

LAB HEAD: Laurent Maillet

PROVIDER: PXD066303 | Pride | 2025-12-08

REPOSITORIES: Pride