PXD021761

PXD021761 is an original dataset announced via ProteomeXchange.

Title	Structural basis for heme-dependent NCoR binding to the transcriptional repressor REV-ERBβ
Description	Heme is the endogenous ligand for the constitutively repressive REV-ERB nuclear receptors, REV-ERBα (NR1D1) and REV-ERBβ (NR1D2), but how heme regulates REV-ERB activity remains unclear. While cellular studies indicate heme is required for the REV-ERBs to bind the corepressor NCoR and repress transcription, fluorescence-based biochemical assays and crystal structures suggest that heme displaces NCoR. Here, we found that heme artifactually influences detection of NCoR interaction in fluorescence-based assays. Using fluorescence-independent methods, including isothermal titration calorimetry, NMR spectroscopy, and XL-MS, we determined that heme remodels the thermodynamic profile of NCoR binding to REV-ERBβ ligand-binding domain (LBD) and directly increases LBD binding affinity for an NCoR interaction motif. We further report two crystal structures of REV-ERBβ LBD cobound to heme and NCoR peptides, which reveal the heme-dependent NCoR binding mode. By resolving previous contradictory biochemical, structural, and cellular studies, our findings should facilitate renewed progress toward understanding heme-dependent REV-ERB activity.
HostingRepository	PRIDE
AnnounceDate	2021-02-25
AnnouncementXML	Submission_2021-02-24_22:13:33.953.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Timothy Strutzenberg
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-09-30 01:16:22	ID requested
1	2021-02-24 12:51:18	announced
⏵ 2	2021-02-24 22:13:34	announced	2021-02-25: Updated project metadata.

10.1126/SCIADV.ABC6479;

Mosure SA, Strutzenberg TS, Shang J, Munoz-Tello P, Solt LA, Griffin PR, Kojetin DJ, . Sci Adv, 7(5):(2021) [pubmed]

submitter keyword: Orphan Nuclear Receptor, Rev-ERb, Ligand Binding, Protein-Protein Interactions

Patrick Robert Griffin
contact affiliation	The Scripps Research Institute Department of Molecular Medicine
contact email	pgriffin@scripps.edu
lab head
Timothy Strutzenberg
contact affiliation	TSRI
contact email	tstrutze@scripps.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2021/02/PXD021761

PRIDE project URI

• PRIDE
  1. PXD021761
     1. Label: PRIDE project
     2. Name: Structural basis for heme-dependent NCoR binding to the transcriptional repressor REV-ERBβ