Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery.

Eukaryotic transcriptional repressors function by recruiting large co-regulatory complexes that target histone deacetylase enzymes to gene promoters/enhancers. Transcriptional repression complexes, assembled by the co-repressor NCoR, and its homologue SMRT, play critical roles in many processes including development and metabolic physiology. The core repression complex involves the recruitment of three proteins: HDAC3, GPS2 and TBL1 to a highly conserved repression domain within SMRT and NCoR. We have used a variety of structural and functional approaches to gain insight into the assembly, stoichiometry and biological role of this complex. We report the crystal structure of the tetrameric oligomerization domain of TBL1, which interacts with both SMRT and GPS2, and the NMR structure of the interface complex between GPS2 and SMRT. These structures, together with computational docking, mutagenesis and functional assays, reveal the assembly mechanism and stoichiometry of the co-repressor complex.

真核转录抑制因子通过招募大型共调节复合物发挥作用，这些复合物将组蛋白去乙酰化酶靶向基因启动子/增强子。由共抑制因子NCoR及其同源物SMRT组装的转录抑制复合物在许多过程中发挥关键作用，包括发育和代谢生理。核心抑制复合物涉及将三种蛋白质：HDAC3、GPS2和TBL1招募到SMRT和NCoR内一个高度保守的抑制结构域。我们使用了多种结构和功能方法来深入了解该复合物的组装、化学计量和生物学作用。我们报道了TBL1的四聚寡聚化结构域的晶体结构，它与SMRT和GPS2都相互作用，以及GPS2和SMRT之间界面复合物的核磁共振结构。这些结构，连同计算对接、诱变和功能测定，揭示了共抑制因子复合物的组装机制和化学计量。