PXD040953-1

PXD040953 is an original dataset announced via ProteomeXchange.

Title	UBR5 Forms Ligand-Dependent Complexes on Chromatin to Regulate Nuclear Hormone Receptor Stability
Description	Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Hormone binding triggers NR activation and their subsequent proteasomal degradation through unknown ligand-dependent ubiquitin ligase machinery. NR degradation is therapeutically relevant. Efficacy of all-trans-retinoic acid (ATRA) for the treatment of acute promyelocytic leukemia requires degradation of the oncogenic fusion between the Promyelocytic Leukemia Protein (PML) with the Retinoic Acid Receptor Alpha (RARA). Here we use CRISPR-based screens to identify the HECT E3 ubiquitin ligase UBR5 as a ligase for PML-RARA and RARA and observe an agonist-dependent association between RARA and UBR5, which occurs directly on chromatin to regulate transcription. We present the cryo-EM structure of full-length human UBR5 and identify a Leu-X-X-Leu-Leu (LxxLL) binding motif that associates with a conserved degron in RARA. A high-resolution crystal structure of the RARA ligand binding domain in complex with this LxxLL motif shows how UBR5 binding is mutually exclusive with nuclear co-activator engagement. We demonstrate that UBR5 utilizes this conserved degron to additionally regulate hormone dependent protein stability for the glucocorticoid, progesterone, and vitamin D receptors. Our work establishes UBR5-driven NR degradation as an integral regulator of transcriptional signaling by nuclear hormones.
HostingRepository	PRIDE
AnnounceDate	2023-07-20
AnnouncementXML	Submission_2023-07-20_08:24:08.511.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	EricFischer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2023-03-17 14:24:39	ID requested
⏵ 1	2023-07-20 08:24:08	announced

Dataset with its publication pending

submitter keyword: nuclear receptors,UBR5, degradation, hormones, chromatin

EricFischer
contact affiliation	Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
contact email	Eric_Fischer@DFCI.HARVARD.EDU
lab head
EricFischer
contact affiliation	Dana-Farber Cancer Institute
contact email	eric_fischer@dfci.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD040953
     1. Label: PRIDE project
     2. Name: UBR5 Forms Ligand-Dependent Complexes on Chromatin to Regulate Nuclear Hormone Receptor Stability