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Structural basis for the versatile interactions of Smad7 with regulator WW domains in TGF-? Pathways.


ABSTRACT: Transforming growth factor (TGF)-? 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-? 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-? and BMP pathways.

SUBMITTER: Aragon E 

PROVIDER: S-EPMC3472128 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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

Aragón Eric E   Goerner Nina N   Xi Qiaoran Q   Gomes Tiago T   Gao Sheng S   Massagué Joan J   Macias Maria J MJ  

Structure (London, England : 1993) 20120823 10


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  ...[more]

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