Structural basis of heteromeric smad protein assembly in TGF-beta signaling.

Chacko BM, Qin BY, Tiwari A, Shi G, Lam S, Hayward LJ, De Caestecker M, Lin K
Mol Cell. 2004 15 (5): 813-23

PMID: 15350224 · DOI:10.1016/j.molcel.2004.07.016

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.

Copyright 2004 Cell Press

MeSH Terms (19)

Animals Biomarkers, Tumor 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

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