Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) form heterodimers that activate target gene transcription by recruiting co-activator complexes in response to ligand binding. The nuclear receptor (NR) co-activator TIF2 mediates this recruitment by interacting with the ligand-binding domain (LBD) of NRs trough the nuclear receptor interaction domain (TIF2NRID) containing three highly conserved α-helical LxxLL motifs (NR-boxes). The precise binding mode of this domain to RXR/RAR is not clear due to the disordered nature of TIF2. Here we present the structural characterization of TIF2NRID by integrating several experimental (NMR, SAXS, CD, SEC-MALS) and computational data. Collectively, the data are in agreement with a largely disordered protein with partially structured regions, including the NR-boxes and their flanking regions, which are evolutionary conserved. NMR and X-ray crystallographic data on TIF2NRID in complex with RXR/RAR reveal a cooperative binding of the three NR-boxes as well as an active role of their flanking regions in the interaction.

中文翻译：

---

内在失调的共激活因子TIF2与视黄酸受体异二聚体（RXR / RAR）的协同相互作用的结构见解

维甲酸受体（RAR）和类维生素X受体（RXR）形成异二聚体，通过响应配体结合募集共活化剂复合物来激活靶基因转录。核受体（NR）共激活因子TIF2通过与包含三个高度保守的α-螺旋LxxLL模体（NR-box）的核受体相互作用域（TIF2NRID）的NRs的配体结合域（LBD）相互作用，介导了这种募集。由于TIF2的无序性质，该域与RXR / RAR的精确结合模式尚不清楚。在这里，我们通过整合几个实验数据（NMR，SAXS，CD，SEC-MALS）和计算数据来介绍TIF2NRID的结构特征。总体而言，这些数据与具有部分结构化区域（包括NR盒及其侧翼区域）的高度无序的蛋白质一致，这是进化保守的。与RXR / RAR配合使用的TIF2NRID的NMR和X射线晶体学数据揭示了三个NR-boxs的协同结合以及其侧翼区在相互作用中的活跃作用。