6wms

Publication Abstract from PubMed

Heme is the endogenous ligand for the constitutively repressive REV-ERB nuclear receptors, REV-ERBalpha (NR1D1) and REV-ERBbeta (NR1D2), but how heme regulates REV-ERB activity remains unclear. Cellular studies indicate that heme is required for the REV-ERBs to bind the corepressor NCoR and repress transcription. However, fluorescence-based biochemical assays suggest that heme displaces NCoR; here, we show that this is due to a heme-dependent artifact. Using ITC and NMR spectroscopy, we show that heme binding remodels the thermodynamic interaction profile of NCoR receptor interaction domain (RID) binding to REV-ERBbeta ligand-binding domain (LBD). We solved two crystal structures of REV-ERBbeta LBD cobound to heme and NCoR peptides, revealing the heme-dependent NCoR binding mode. ITC and chemical cross-linking mass spectrometry reveals a 2:1 LBD:RID stoichiometry, consistent with cellular studies showing that NCoR-dependent repression of REV-ERB transcription occurs on dimeric DNA response elements. Our findings should facilitate renewed progress toward understanding heme-dependent REV-ERB activity.

Structural basis for heme-dependent NCoR binding to the transcriptional repressor REV-ERBbeta.,Mosure SA, Strutzenberg TS, Shang J, Munoz-Tello P, Solt LA, Griffin PR, Kojetin DJ Sci Adv. 2021 Jan 27;7(5):eabc6479. doi: 10.1126/sciadv.abc6479. Print 2021 Jan. PMID:33571111^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.