PXD066303

PXD066303 is an original dataset announced via ProteomeXchange.

Title	Allosteric regulation of BH3-in-groove interactions by tail anchors of BCL-xL complexes limits BH3 mimetic antagonism
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-12-08
AnnouncementXML	Submission_2025-12-07_17:29:44.624.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	François Guillonneau
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	methylthiolated residue; monohydroxylated residue
Instrument	TripleTOF 5600

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-18 02:17:51	ID requested
⏵ 1	2025-12-07 17:29:45	announced

10.1038/s41467-025-65509-1;

Maillet L, F, é, tiveau A, Lalier L, Martin N, Barill, é, -Nion S, Guette C, Gautier F, T, é, letch, é, a S, Juin PP, Allosteric regulation of BH3-in-groove interactions by tail anchors of BCL-xL complexes limits BH3 mimetic antagonism. Nat Commun, 16(1):10621(2025) [pubmed]

submitter keyword: PUMA, Tail anchors, BCL-xL, BAX, TripleTOF 5600+, BH3 mimetic,SWATH

Laurent Maillet
contact affiliation	Nantes Université, INSERM, CNRS, CRCI2NA, U1307, UMR6075, F-44000 Nantes, France.
contact email	laurent.maillet@inserm.fr
lab head
François Guillonneau
contact affiliation	Institut de Cancerologie de l'Ouest (ICO) Angers
contact email	francois.guillonneau@inserm.fr
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD066303
     1. Label: PRIDE project
     2. Name: Allosteric regulation of BH3-in-groove interactions by tail anchors of BCL-xL complexes limits BH3 mimetic antagonism