Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, OH 45267 USA.
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, OH 45267 USA.
Structure. 2014 Jan 7;22(1):70-81. doi: 10.1016/j.str.2013.10.010. Epub 2013 Nov 27.
Notch refers to a highly conserved cell-to-cell signaling pathway with essential roles in embryonic development and tissue maintenance. Dysfunctional signaling causes human disease, highlighting the importance of pathway regulation. Notch signaling ultimately results in the activation of target genes, which is regulated by the nuclear effector CSL (CBF-1/RBP-J, Su(H), Lag-1). CSL dually functions as an activator and a repressor of transcription through differential interactions with coactivator or corepressor proteins, respectively. Although the structures of CSL-coactivator complexes have been determined, the structures of CSL-corepressor complexes are unknown. Here, using a combination of structural, biophysical, and cellular approaches, we characterize the structure and function of CSL in complex with the corepressor KyoT2. Collectively, our studies provide molecular insights into how KyoT2 binds CSL with high affinity and competes with coactivators, such as Notch, for binding CSL. These studies are important for understanding how CSL functions as both an activator and a repressor of transcription of Notch target genes.
Notch 是一种高度保守的细胞间信号通路，在胚胎发育和组织维持中具有重要作用。信号通路功能失调会导致人类疾病，这凸显了对通路调控的重要性。Notch 信号通路最终导致靶基因的激活，这受核效应因子 CSL（CBF-1/RBP-J、Su(H)、Lag-1）的调控。CSL 通过与共激活或核心抑制蛋白的不同相互作用，双重发挥转录激活和抑制的作用。尽管已经确定了 CSL-共激活复合物的结构，但 CSL-核心抑制复合物的结构尚不清楚。在这里，我们使用结构、生物物理和细胞方法的组合，来表征 CSL 与核心抑制因子 KyoT2 形成复合物的结构和功能。总的来说，我们的研究为 KyoT2 如何以高亲和力结合 CSL 以及如何与 Notch 等共激活因子竞争结合 CSL 提供了分子见解。这些研究对于理解 CSL 如何作为 Notch 靶基因转录的激活子和抑制子发挥作用至关重要。
