PXD070252

PXD070252 is an original dataset announced via ProteomeXchange.

Title	4-ONE as a Chemoselective Biological Glue for Site-Resolved Protein Crosslinking and Proteomic Profiling
Description	Protein crosslinking governs structure, stability, and interaction networks in biology, yet current chemical crosslinkers lack selectivity, produce heterogeneous products, and require pre-installed cleavable handles for analysis. Here, we report a conceptually distinct strategy that harnesses the intrinsic reactivity of the lipid peroxidation product 4-oxo-nonenal (4-ONE) to enable selective and programmable protein crosslinking. We show that 4-ONE operates as a biological glue that follows defined chemical logic: an initial Michael addition to cysteine activates a latent aldehyde function, which subsequently reacts with lysine to form a stable pyrrole crosslink. Building on this reactivity, we introduce COSMIC (Crosslink Oxidation to Sulfoxide for Mass-Cleavable Interactomics), a late-stage oxidation strategy that transforms stable crosslinks into mass-cleavable sulfoxides that generate distinct fragmentation signatures for lysine and cysteine, enabling direct site-resolution by LC-MS/MS. This platform enables peptide stapling and macrocyclization, protein conjugation, identification of hyperreactive Lys and Cys sites prone to 4-ONE modification, and live-cell crosslinking analysis. Together, these results establish a generalizable chemical strategy for decoding metabolite-driven protein crosslinking and its impact on toxicity.
HostingRepository	PRIDE
AnnounceDate	2026-05-26
AnnouncementXML	Submission_2026-05-25_17:19:48.977.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Riley Hughes
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-11-03 15:02:10	ID requested
⏵ 1	2026-05-25 17:19:49	announced

Dataset with its publication pending

submitter keyword: None

Monika Raj
contact affiliation	Emory University
contact email	monika.raj@emory.edu
lab head
Riley Hughes
contact affiliation	Emory University
contact email	riley.hughes@emory.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/2026/05/PXD070252

PRIDE project URI

• PRIDE
  1. PXD070252
     1. Label: PRIDE project
     2. Name: 4-ONE as a Chemoselective Biological Glue for Site-Resolved Protein Crosslinking and Proteomic Profiling