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Phosphorylation-induced trimerization regulates Smad3 activity in the TGF- signal transduction pathway. Shown here is a model of the transforming growth factor beta (TGF-) receptor complex. The complex consists of the type I transmembrane receptor kinase (green), type II transmembrane receptor kinase (pink), TGF- ligand (dark blue), SARA (yellow), and Smad 3 (subdomains colored cyan and red). Ligand binding triggers phosphorylation of the GS loop residues (pink spheres) in the type I kinase by the type II kinase. The type I kinase then phosphorylates the Smad3 C-terminal tail (pink). Phosphorylation of Smad3 requires recruitment by SARA, as well as interactions between the Smad3 L3 loop residues (red spheres) and the type I kinase L45 loop residues (blue spheres). Upon phosphorylation, Smad3 undergoes conformational changes, which favor its dissociation from SARA. The ectodomain/ligand portion was modeled after recently published crystal structures. The cytoplasmic portion was derived from docking the kinase domains to the crystal structure of a dimeric Smad3/SARA complex. (For details, see Qin et al., p. 1950.)