Structural basis for the versatile interactions of Smad7 with regulator WW domains in TGF-β pathways

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Abstract

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. © 2012 Elsevier Ltd.

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Aragón, E., Goerner, N., Xi, Q., Gomes, T., Gao, S., Massagué, J., & MacIas, M. J. (2012). Structural basis for the versatile interactions of Smad7 with regulator WW domains in TGF-β pathways. Structure, 20(10), 1726–1736. https://doi.org/10.1016/j.str.2012.07.014

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