PXD043732-2

PXD043732 is an original dataset announced via ProteomeXchange.

Title	Profiling nuclear cysteine ligandability and effects on nuclear localization using proximity labeling-coupled chemoproteomics
Description	The nucleus controls cell growth and reproduction by well-orchestrated interactions between nuclear proteins and chromatin. Mutations that result in the dysregulation of these chromatin-associated proteins are known to lead to the onset of numerous diseases. Many of these nuclear proteins have remained recalcitrant to traditional non-covalent small-molecule ligand discovery. Covalent ligands can provide a promising approach for targeting proteins such as transcription factors that lack ordered small-molecule binding pockets. Here, we present a chemoproteomic platform that couples proximity labeling (PL) using a Histone-TurboID (His-TID) construct with competitive isoTOP-ABPP to identify ligandable nuclear cysteines. Application of covalent scout fragments, KB02 and KB05, revealed ligandable cysteine sites on diverse proteins involved in transcriptional regulation, spindle assembly, and DNA repair. To identify functional liganding events that alter target-protein association with chromatin, we monitor the effects of KB02 and KB05 on the chromatin-associated proteome. Importantly, we identify proteins that show both increased and decreased association with chromatin in the presence of the covalent fragments. Notably, the Parkinson disease protein 7 (PARK7) showed increased nuclear localization and association with chromatin upon covalent liganding at Cys106 by KB02. Together, our PL-assisted nuclear-focused chemoproteomic platform provides us insights into nuclear cysteine ligandability and the functional effects of ligand binding on chromatin association, thereby furthering our understanding of the potentially druggability of the nuclear proteome.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:24:53.659.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Qianni Peng
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 240

Revision	Datetime	Status	ChangeLog Entry
0	2023-07-12 15:15:44	ID requested
1	2024-01-23 22:10:58	announced
⏵ 2	2024-10-22 06:24:54	announced	2024-10-22: Updated project metadata.

10.1016/J.CHEMBIOL.2023.11.010;

submitter keyword: chromatin association, TurboID,Nuclear cysteine ligandability, proximity labeling

Eranthie Weerapana
contact affiliation	Department of Chemistry, Boston College, USA
contact email	eranthie@bc.edu
lab head
Qianni Peng
contact affiliation	Department of Chemistry, Boston College
contact email	pengqb@bc.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD043732
     1. Label: PRIDE project
     2. Name: Profiling nuclear cysteine ligandability and effects on nuclear localization using proximity labeling-coupled chemoproteomics