PXD016059

PXD016059 is an original dataset announced via ProteomeXchange.

Title	A Redox Switch Regulates the Structure and Function of Anti-Apoptotic BFL-1
Description	BCL-2 family proteins control cell fate by regulating the mitochondrial apoptotic pathway. Anti-apoptotic members suppress cell death by capturing pro-apoptotic α-helices in a surface groove, a mechanism hijacked by cancer cells to enforce cellular immortality. We previously identified and harnessed a unique cysteine (C55) in the canonical groove of anti-apoptotic BFL-1 to selectively neutralize its oncogenic activity using a covalent stapled-peptide inhibitor. Here, we find that disulfide bonding between a native cysteine pair at the interface between the groove (C55) and C-terminal α9 helix (C175) operates as a redox switch to control the accessibility and functionality of the anti-apoptotic pocket. Hydrogen deuterium exchange mass spectrometry was used to characterize a construct of BFL-1 deleting the C-terminus and thus C175 (BFL-1ΔC C55), as well as full length BFL-1 (BFL-1 C55/C175) in both oxidation states. Reducing the C55-C175 disulfide bond triggers a cascade of structure-function changes that includes release of α9 for membrane translocation, exposure of the groove for α-helical interaction, and resultant blockade of mitochondrial membrane permeabilization by pro-apoptotic BAX. Thus, we identify a unique mechanism of conformational control over anti-apoptotic activity by a redox switch in BFL-1.
HostingRepository	PRIDE
AnnounceDate	2020-06-17
AnnouncementXML	Submission_2020-07-18_18:39:13.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	John R. Engen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2019-10-29 02:39:57	ID requested
1	2020-06-16 22:55:25	announced
⏵ 2	2020-07-18 18:39:13	announced	2020-07-19: Updated publication reference for PubMed record(s): 32661419.

Korshavn KJ, Wales TE, Bird GH, Engen JR, Walensky LD, A redox switch regulates the structure and function of anti-apoptotic BFL-1. Nat Struct Mol Biol, 27(9):781-789(2020) [pubmed]

submitter keyword: BCL-2 family, apoptosis, conformational change, hydrogen deuterium exchange, HDXMS

John R. Engen
contact affiliation	Department of Chemistry & Chemical Biology, Northeastern University
contact email	j.engen@northeastern.edu
lab head
John R. Engen
contact affiliation	Northeastern University
contact email	j.engen@northeastern.edu
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/2020/06/PXD016059

PRIDE project URI

• PRIDE
  1. PXD016059
     1. Label: PRIDE project
     2. Name: A Redox Switch Regulates the Structure and Function of Anti-Apoptotic BFL-1