Structural Basis for the Versatile Interactions of Smad7 with Regulator WW Domains in TGF-β Pathways
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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.
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Several mechanisms have been proposed for how Yap or Taz interact with Smads, including binding to Smad7, promotion of Smad1 transcriptional action, and effects on Smad2/3 localisation.
“Several mechanisms have been proposed that can explain how Yap or Taz can interact with Smads. These include the binding of Yap to the inhibitory Smad7 (7, 49), the promotion of Smad1 transcriptional action by Yap binding (3), and an effect of Yap and Taz on Smad2/3 localisation (137).”
From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [7]
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- Authors
- Aragón, E., Goerner, N., Xi, Q., Gomes, T., Gao, S., Massagué, J., & Macias, M. J.
- Affiliations
- Institute for Research in Biomedicine (ES)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Massagué, Joan
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 20
- Issue
- 10
- Pages
- 1726-1736
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC3472128
- OpenAlex
- W2043685957
- Cited by
- 99
- References
- 46
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 5 · 2022: 2 · 2021: 12 · 2020: 10 · 2019: 10 · 2018: 7 · 2017: 10 · 2016: 6 · 2015: 14 · 2014: 13 · 2013: 3 · 2012: 1
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R37CA034610, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- Smad7, WW domain, TGF-beta signaling, BMP signaling, Smad proteins, YAP, Smurf1, Smurf2, NEDD4L, PY motif, protein-protein interaction, ubiquitination, negative feedback regulation, protein structure
- MeSH terms
- Nedd4 Ubiquitin Protein Ligases, Calorimetry, Humans, Hydrogen Bonding, Models, Molecular, Magnetic Resonance Spectroscopy, Nuclear Proteins, Phosphorylation, Protein Binding, Protein Processing, Post-Translational, Surface Properties, Transcription Factors, Signal Transduction, Transforming Growth Factor beta, Protein Structure, Secondary, Cell Cycle Proteins, Amino Acid Motifs, Ubiquitin-Protein Ligases, Smad7 Protein, Protein Interaction Domains and Motifs, Endosomal Sorting Complexes Required for Transport
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