title: Structural basis for the versatile interactions of Smad7 with regulator WW domains in TGF-β Pathways.
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.
authors.affiliation: Structural and Computational Biology Programme, Institute for Research in Biomedicine, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
authors.forename: Eric
authors.initials: E
authors.lastname: Aragón
authors.forename: Nina
authors.initials: N
authors.lastname: Goerner
authors.forename: Qiaoran
authors.initials: Q
authors.lastname: Xi
authors.forename: Tiago
authors.initials: T
authors.lastname: Gomes
authors.forename: Sheng
authors.initials: S
authors.lastname: Gao
authors.forename: Joan
authors.initials: J
authors.lastname: Massagué
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Macias
mesh_terms: D020816:Amino Acid Motifs; D002151:Calorimetry; D018797:Cell Cycle Proteins; D056827:Endosomal Sorting Complexes Required for Transport / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D000075702:Nedd4 Ubiquitin Protein Ligases; D009687:Nuclear Proteins / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D015398:Signal Transduction; D051906:Smad7 Protein / Q000737:chemistry*; D013499:Surface Properties; D014157:Transcription Factors / Q000737:chemistry; D016212:Transforming Growth Factor beta / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry
chemical_list: D018797:Cell Cycle Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D009687:Nuclear Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C456659:YY1AP1 protein, human; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618485:Nedd4L protein, human; C498342:SMURF1 protein, human; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases