PXD027288

PXD027288 is an original dataset announced via ProteomeXchange.

Title	Dynamic re-configuration of pro-apoptotic BAK on membranes
Description	BAK and BAX, the effectors of intrinsic apoptosis, undergo major reconfiguration to an activated conformer that self-associates to damage mitochondria and cause cell death. However, the dynamic structural mechanisms that describe this reconfiguration in the presence of a membrane have yet to be fully elucidated. To explore the metamorphosis of membrane-bound BAK, we employed hydrogen-deuterium exchange mass spectrometry (HDX-MS) on liposomes comprising mitochondrial lipids. The HDX-MS profile of BAK on a membrane was broadly consistent with the known solution structures of inactive BAK. Following activation, HDX-MS resolved major reconfigurations in BAK. Mutagenesis led by our HDX-MS profiling revealed that the BCL-2 homology (BH) 4 domain maintains BAK in its inactive conformation and disrupting this was sufficient for constitutive BAK activation. Moreover, the entire BAK N-terminus that precedes the BAK oligomerisation domains became disordered post-activation and remained disordered in the activated oligomer. Cleavage of the N-terminus potentiated BAK-mediated membrane permeabilisation on liposomes and mitochondria. Together, HDX-MS reveals new insights into the dynamic nature of BAK activating conformation change in a membrane that will reveal new opportunities for therapeutic targeting.
HostingRepository	PRIDE
AnnounceDate	2021-08-09
AnnouncementXML	Submission_2021-08-09_04:11:14.584.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jarrod Sandow
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2021-07-14 03:44:37	ID requested
⏵ 1	2021-08-09 04:11:14	announced

Dataset with its publication pending

submitter keyword: HDX, Bak, apoptosis

Grant Dewson
contact affiliation	Laboratory Head Ubiquitin Signalling Division
contact email	dewson@wehi.edu.au
lab head
Jarrod Sandow
contact affiliation	WEHI
contact email	sandow@wehi.edu.au
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2021/08/PXD027288

PRIDE project URI

• PRIDE
  1. PXD027288
     1. Label: PRIDE project
     2. Name: Dynamic re-configuration of pro-apoptotic BAK on membranes