Structural Insights into Smad Function and Specificity

Abstract

Smads contain two conserved domains, MH1 and MH2. The MH1 domain of R-Smads (except Smad2) and Smad4 adopts a compact globular fold and recognizes specific DNA sequences via a novel-hairpin. The fact that each MH1 domain only recognizes 3-4 base pairs of DNA governs the need for Smads to cooperate among each other and with other DNA-binding proteins. The MH2 domain forms a central-sandwich capped by a three-helix bundle on one end and a loop/helix region on the other end. Structural analyses of TGF-receptors and the MH2 domains have revealed an essential and conserved theme in signaling. Phosphorylation of the GS region in the type I receptor results in the generation of pS/pT-X-pS motifs, which facilitate recruitment of R-Smads by binding to a positively charged and conserved surface pocket on R-Smads. After phosphorylation, the pS-X-pS motif at the C-terminus of R-Smads assists their dissociation from the receptors and aids formation of homomeric as well as heteromeric Smad complexes by binding to the same surface pocket of neighboring Smads. The MH2 domain interacts with a large number of proteins through a hydrophobic surface groove known as hydrophobic corridor