Smad proteins play a key role in transforming growth factor-β (TGF-β) signaling pathways, and structural studies can help unravel how related members of the Smad family can induce different signaling outcomes. The receptor-regulated Smads (R-Smads) are each involved in a specific signaling pathway, and the activation of specific TGF-β receptors mediates phosphorylation of specific R-Smads. Phosphorylated R-Smads heterodimerize with co-mediator Smads (co-Smads), and such complexes translocate into the nucleus and activate target genes. Smad2, an R-Smad that acts as a tumor suppressor in humans, is recruited to its TGF-β receptor by the protein SARA (Smad anchor for receptor activation). SARA does not interact with the R-Smads Smad1 or Smad5 despite an 80% sequence identity with Smad2. Wu et al. have determined a structure of the Smad2 MH2 domain, which is involved in receptor recognition, with the Smad-binding domain of SARA that reveals the molecular basis for the specificity of the Smad2 interaction with SARA. Comparison of R-Smad and co-Smad structures provide insight into how R-Smads are recognized by receptors.
Wu, G., Chen, Y-G., Ozdamar, B., Gyuricza, C.A., Chong, P.A., Wrana, J.L., Massagué, J., and Shi, Y. (2000) Structural basis of Smad2 recognition by the Smad anchor for receptor activation. Science 287: 92-97. [Abstract] [Full Text]