Abstract
Ligand-induced phosphorylation of the receptor-regulated Smads (R-Smads) is essential in the receptor Ser/Thr kinase-mediated TGF-beta signaling. The crystal structure of a phosphorylated Smad2, at 1.8 A resolution, reveals the formation of a homotrimer mediated by the C-terminal phosphoserine (pSer) residues. The pSer binding surface on the MH2 domain, frequently targeted for inactivation in cancers, is highly conserved among the Co- and R-Smads. This finding, together with mutagenesis data, pinpoints a functional interface between Smad2 and Smad4. In addition, the pSer binding surface on the MH2 domain coincides with the surface on R-Smads that is required for docking interactions with the serine-phosphorylated receptor kinases. These observations define a bifunctional role for the MH2 domain as a pSer-X-pSer binding module in receptor Ser/Thr kinase signaling pathways.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Motifs
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Amino Acid Sequence
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Animals
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Binding Sites
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Crystallography, X-Ray
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DNA-Binding Proteins / chemistry*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Humans
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Models, Biological
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Models, Molecular
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Molecular Sequence Data
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Mutation / genetics
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Neoplasms / genetics
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Phosphorylation
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Phosphoserine / metabolism*
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Protein Serine-Threonine Kinases / metabolism
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Protein Structure, Quaternary
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Protein Structure, Tertiary
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Sequence Alignment
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Signal Transduction / drug effects*
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Smad2 Protein
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Smad4 Protein
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Structure-Activity Relationship
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Trans-Activators / chemistry*
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transforming Growth Factor beta / pharmacology*
Substances
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DNA-Binding Proteins
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SMAD2 protein, human
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SMAD4 protein, human
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Smad2 Protein
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Smad4 Protein
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Trans-Activators
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Transforming Growth Factor beta
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Phosphoserine
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Protein Serine-Threonine Kinases