Structural and Computational Biology Programme, Institute for Research in Biomedicine, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
Structure. 2012 Oct 10;20(10):1726-36. doi: 10.1016/j.str.2012.07.014. Epub 2012 Aug 23.
Transforming growth factor (TGF)-β and BMP signaling is mediated by Smads 1-5 (R-Smads and Co-Smads) and inhibited by Smad7, a major hub of regulation of TGF-β and BMP receptors by negative feedback and antagonistic signals. The transcription coactivator YAP and the E3 ubiquitin ligases Smurf1/2 and Nedd4L target R-Smads for activation or degradation, respectively. Pairs of WW domain in these regulators bind PY motifs and adjacent CDK/MAPK and GSK3 phosphorylation sites in R-Smads in a selective and regulated manner. In contrast, here we show that Smad7 binds YAP, Smurf1, Smurf2, and Nedd4L constitutively, the binding involving a PY motif in Smad7 and no phosphorylation. We also provide a structural basis for how regulators that use WW domain pairs for selective interactions with R-Smads, resort to one single versatile WW domain for binding Smad7 to centralize regulation in the TGF-β and BMP pathways.
转化生长因子 (TGF)-β 和 BMP 信号转导由 Smads 1-5（R-Smads 和 Co-Smads）介导，并受 Smad7 抑制，Smad7 是 TGF-β 和 BMP 受体负反馈和拮抗信号调节的主要枢纽。转录共激活因子 YAP 和 E3 泛素连接酶 Smurf1/2 和 Nedd4L 分别靶向 R-Smads 进行激活或降解。这些调节剂中的 WW 结构域对 R-Smads 中的 PY 基序和相邻的 CDK/MAPK 和 GSK3 磷酸化位点具有选择性和调节性结合。相比之下，在这里我们表明 Smad7 与 YAP、Smurf1、Smurf2 和 Nedd4L 持续结合，结合涉及 Smad7 中的 PY 基序且不涉及磷酸化。我们还为如何使用 WW 结构域对 R-Smads 进行选择性相互作用的调节剂提供了结构基础，这些调节剂使用单个通用 WW 结构域与 Smad7 结合，从而集中 TGF-β 和 BMP 途径中的调节。
