Structural basis of heteromeric smad protein assembly in TGF-beta signaling.
The formation of protein complexes between phosphorylated R-Smads and Smad4 is a central event in the TGF-beta signaling pathway. We have determined the crystal structure of two R-Smad/Smad4 complexes, Smad3/Smad4 to 2.5 angstroms, and Smad2/Smad4 to 2.7 angstroms. Both complexes are heterotrimers, comprising two phosphorylated R-Smad subunits and one Smad4 ... subunit, a finding that was corroborated by isothermal titration calorimetry and mutational studies. Preferential formation of the R-Smad/Smad4 heterotrimer over the R-Smad homotrimer is largely enthalpy driven, contributed by the unique presence of strong electrostatic interactions within the heterotrimeric interfaces. The study supports a common mechanism of Smad protein assembly in TGF-beta superfamily signaling.
Mesh Terms:
Animals, COS Cells, Crystallography, X-Ray, DNA-Binding Proteins, Hot Temperature, Macromolecular Substances, Models, Molecular, Molecular Conformation, Phosphorylation, Polymers, Protein Structure, Tertiary, Protein Subunits, Signal Transduction, Smad2 Protein, Smad3 Protein, Temperature, Trans-Activators, Transforming Growth Factor beta, Tumor Markers, Biological
Animals, COS Cells, Crystallography, X-Ray, DNA-Binding Proteins, Hot Temperature, Macromolecular Substances, Models, Molecular, Molecular Conformation, Phosphorylation, Polymers, Protein Structure, Tertiary, Protein Subunits, Signal Transduction, Smad2 Protein, Smad3 Protein, Temperature, Trans-Activators, Transforming Growth Factor beta, Tumor Markers, Biological
Mol. Cell
Date: Sep. 10, 2004
PubMed ID: 15350224
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