The TGF beta receptor activation process: An inhibitor- to substrate-binding switch

The type I TGF beta receptor (T betaR-I) is activated by phosphorylation of the GS region, a conserved juxtamembrane segment located just N-terminal t o the kinase domain. We have studied the molecular mechanism of receptor ac tivation using a homogeneously tetraphosphorylated form of T betaR-1, prepa red using protein semisynthesis. Phosphorylation of the GS region dramatica lly enhances the specificity of T betaR-I for the critical C-terminal serin es of Smad2. In addition, tetraphosphorylated T betaR-I is bound specifical ly by Smad2 in a phosphorylation-dependent manner and is no longer recogniz ed by the inhibitory protein FKBP12. Thus, phosphorylation activates T beta R-I by switching the GS region from a binding site for an inhibitor into a binding surface for substrate. Our observations suggest that phosphoserine/ phosphothreonine-dependent localization is a key feature of the T betaR-I/S mad activation process.