Structural basis of heteromeric smad protein assembly in TGF-beta signaling
Biochemistry & Molecular Pharmacology
Graduate School of Biomedical Sciences; Department of Neurology; Department of Biochemistry and Molecular Pharmacology
Life Sciences | Medicine and Health Sciences
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.
DOI of Published Version
Mol Cell. 2004 Sep 10;15(5):813-23. Link to article on publisher's site
Chacko, Benoy Maramparambil; Qin, Bin Y.; Tiwari, Ashutosh; Shi, Genbin; Lam, Suvana S.; Hayward, Lawrence J.; De Caestecker, Mark; and Lin, Kai, "Structural basis of heteromeric smad protein assembly in TGF-beta signaling" (2004). GSBS Student Publications. 193.