PXD061730

PXD061730 is an original dataset announced via ProteomeXchange.

Title	PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates
Description	The E3 ligase substrate adapter cereblon (CRBN), the primary target of clinical agents thalidomide and lenalidomide, recognizes endogenous substrates bearing the C-terminal cyclic imide modification. Although C-terminal cyclic imides can form spontaneously, an enzyme that regulates the formation of these modifications and thereby promotes a biological pathway connecting substrates to CRBN is unknown. Here, we report that protein carboxymethyltransferase (PCMT1) promotes formation of the C-terminal cyclic imide on C-terminal asparagine residues of CRBN substrates. PCMT1 and CRBN regulate the levels of metabolic enzymes glutamine synthetase (GLUL) and inorganic pyrophosphatase 1 (PPA1) in vitro, in cells, and in vivo, and this regulation is associated with the proepileptic phenotype of CRBN knockout mouse models. The discovery of an enzyme that regulates CRBN substrates through the C-terminal cyclic imide modification reveals a previously unknown biological pathway that is perturbed by thalidomide derivatives and provides a biochemical basis connecting multiple biological processes to CRBN.
HostingRepository	PRIDE
AnnounceDate	2025-12-05
AnnouncementXML	Submission_2025-12-05_06:18:47.666.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christina Woo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2025-03-11 19:53:08	ID requested
⏵ 1	2025-12-05 06:18:48	announced

10.1038/S41589-025-02106-9;

submitter keyword: CRBN, PCMT1, C-terminal cyclic imide, GLUL, PPA1

Christina M. Woo
contact affiliation	Department of Chemistry and Chemical Biology, Harvard University
contact email	cwoo@chemistry.harvard.edu
lab head
Christina Woo
contact affiliation	Harvard University
contact email	cwoo@chemistry.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD061730
     1. Label: PRIDE project
     2. Name: PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates