PXD034248

PXD034248 is an original dataset announced via ProteomeXchange.

Title	The E3 ubiquitin ligase adaptor cereblon targets the C-terminal cyclic imide degron
Description	The E3 ligase factor cereblon (CRBN) is a target of thalidomide and lenalidomide, which are therapeutic agents used in the treatment of hematopoietic malignancies and as ligands for targeted protein degradation. These agents are proposed to mimic a naturally occurring degron; however, the structural motif recognized by the thalidomide-binding domain of CRBN is unknown. Here, we report that C-terminal cyclic imides, post-translational modifications that arise from intramolecular cyclization of glutamine or asparagine residues, are degrons for CRBN. Dipeptides bearing the cyclic imide degron are substitutes for thalidomide when embedded within bifunctional small molecule degraders. Installation of the degron to the C-terminus of proteins induces CRBN-dependent ubiquitylation and degradation in vitro and in cells. C-Terminal cyclic imides are previously underappreciated post-translational modifications found throughout the human proteome that are endogenously recognized and removed by CRBN. The discovery of the cyclic imide degron defines a novel regulatory process controlled by these modifications, which may impact the development of therapeutic agents that engage CRBN.
HostingRepository	PRIDE
AnnounceDate	2022-07-28
AnnouncementXML	Submission_2022-07-28_04:02:37.482.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: 9606;
ModificationList	dehydrated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos; LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2022-06-01 05:12:49	ID requested
⏵ 1	2022-07-28 04:02:37	announced

Dataset with its publication pending

submitter keyword: Cereblon, degron, cyclic imide, PROTAC

Christina 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. PXD034248
     1. Label: PRIDE project
     2. Name: The E3 ubiquitin ligase adaptor cereblon targets the C-terminal cyclic imide degron