Journal
MOLECULAR CELL
Volume 8, Issue 3, Pages 671-682Publisher
CELL PRESS
DOI: 10.1016/S1097-2765(01)00332-X
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Funding
- NCI NIH HHS [CA34610] Funding Source: Medline
- NIGMS NIH HHS [GM5584301] Funding Source: Medline
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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 to the kinase domain. We have studied the molecular mechanism of receptor activation using a homogeneously tetraphosphorylated form of T betaR-1, prepared using protein semisynthesis. Phosphorylation of the GS region dramatically enhances the specificity of T betaR-I for the critical C-terminal serines of Smad2. In addition, tetraphosphorylated T betaR-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 betaR-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/Smad activation process.
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