+Search query
-Structure paper
Title | Interplay of Protein Disorder in Retinoic Acid Receptor Heterodimer and Its Corepressor Regulates Gene Expression. |
---|---|
Journal, issue, pages | Structure, Vol. 27, Issue 8, Page 1270-11285.e6, Year 2019 |
Publish date | Aug 6, 2019 |
Authors | Tiago N Cordeiro / Nathalie Sibille / Pierre Germain / Philippe Barthe / Abdelhay Boulahtouf / Fréderic Allemand / Rémy Bailly / Valérie Vivat / Christine Ebel / Alessandro Barducci / William Bourguet / Albane le Maire / Pau Bernadó / |
PubMed Abstract | In its unliganded form, the retinoic acid receptor (RAR) in heterodimer with the retinoid X receptor (RXR) exerts a strong repressive activity facilitated by the recruitment of transcriptional ...In its unliganded form, the retinoic acid receptor (RAR) in heterodimer with the retinoid X receptor (RXR) exerts a strong repressive activity facilitated by the recruitment of transcriptional corepressors in the promoter region of target genes. By integrating complementary structural, biophysical, and computational information, we demonstrate that intrinsic disorder is a required feature for the precise regulation of RAR activity. We show that structural dynamics of RAR and RXR H12 regions is an essential mechanism for RAR regulation. Unexpectedly we found that, while mainly disordered, the corepressor N-CoR presents evolutionary conserved structured regions involved in transient intramolecular contacts. In the presence of RXR/RAR, N-CoR exploits its multivalency to form a cooperative multisite complex that displays equilibrium between different conformational states that can be tuned by cognate ligands and receptor mutations. This equilibrium is key to preserving the repressive basal state while allowing the conversion to a transcriptionally active form. |
External links | Structure / PubMed:31178221 |
Methods | SAS (X-ray synchrotron) |
Structure data | SASDF34: Free Nuclear receptor CoRepressor NID (spanning from residue Gln2059 to Glu2325) SASDF44: RXR/RAR Heterodimer : N-CoRNID Complex (1:1) (Nuclear receptor CoRepressor 1; Nuclear Receptor Interaction Domain (NID), N-CoR-NID + Retinoid-X receptor alpha (RXR-alpha) Ligand Binding Domain (LBD), RXR + Retinoic acid receptor alpha (RAR-alpha) Ligand binding domain (LDB), RAR) SASDF54: RXRΔH12/RAR Heterodimer : N-CoRNID Complex (1:1) SASDF64: RXR/RAR Heterodimer : N-CoRNID Complex (1:1) with RAR inverse agonist (BMS493) SASDF74: RXR/RARI396E Heterodimer : N-CoRNID Complex (1:1) SASDF84: RXR/RAR Heterodimer : N-CoRNID Complex (1:1) with RAR agonist (Am580) |
Source |
|