PXD077887-1

PXD077887 is an original dataset announced via ProteomeXchange.

Title	Reprogramming the Lipid Peroxidation Product 4-ONE as a Chemoselective Cleavable Crosslinker
Description	Nature builds and stabilizes proteins through covalent biological glues, yet the logic and traceability of metabolite-driven crosslinking remain obscure. Here we reprogram the lipid peroxidation product 4-oxo-nonenal (4-ONE) into a metabolite-derived Cys-Lys biological glue and mass-cleavable crosslinker. Through a chemoselective two-step pathway, Michael addition to cysteine activates a latent aldehyde that cyclizes with lysine to form a stable pyrrole linkage under physiological conditions. Late-stage oxidation converts this linkage into a mass-cleavable pyrrole sulfoxide, establishing COSMIc (Crosslink Oxidation to Sulfoxide for Mass-Cleavable Interactomics) for site-resolved identification of linked residues through diagnostic sulfenic acid and dehydroalanine fragments. Beyond peptide stapling, macrocyclization, late-stage functionalization, selective protein modification, and illuminating hyperreactive Lys and Cys residues that define 4-ONE reactivity, COSMIc enables detection of structurally informative crosslinks in proteins, proteomes and the human 26S proteasome, where peroxide-induced sulfoxide formation markedly improves fragment assignment and residue-pair confidence. Together, these findings transform 4-ONE from a toxic electrophile into a programmable covalent connector for structural proteomics, covalent mapping and interactome analysis.
HostingRepository	PRIDE
AnnounceDate	2026-06-22
AnnouncementXML	Submission_2026-06-22_03:47:31.361.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Anthony Ciancone
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2026-04-30 14:21:36	ID requested
⏵ 1	2026-06-22 03:47:31	announced

Dataset with its publication pending

submitter keyword: 4-one, peroxidation, mass spectrometry, crosslink,lipid

Francis J. O'Reilly
contact affiliation	Lab Head
contact email	francis.oreilly@stjude.org
lab head
Anthony Ciancone
contact affiliation	NCI Post-Doctoral Researcher
contact email	cianconeam@nih.gov
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD077887
     1. Label: PRIDE project
     2. Name: Reprogramming the Lipid Peroxidation Product 4-ONE as a Chemoselective Cleavable Crosslinker