The TGF beta receptor activation process: an inhibitor- to substrate-binding switch.
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Huse M, Muir TW, Xu L, Chen YG, Kuriyan J, Massague J
The TGF beta receptor activation process: an inhibitor- to substrate-binding switch.
Mol Cell. 2001 Sep;8(3):671-82.
- PubMed ID
- 11583628 [ View in PubMed]
- Abstract
The type I TGF beta receptor (T beta R-I) is activated by phosphorylation of the GS region, a conserved juxtamembrane segment located just N-terminal to the kinase domain. We have studied the molecular mechanism of receptor activation using a homogeneously tetraphosphorylated form of T beta R-I, prepared using protein semisynthesis. Phosphorylation of the GS region dramatically enhances the specificity of T beta R-I for the critical C-terminal serines of Smad2. In addition, tetraphosphorylated T beta R-I is bound specifically by Smad2 in a phosphorylation-dependent manner and is no longer recognized 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 beta R-I/Smad activation process.