The TGFβ receptor activation process: An inhibitor- to substrate-binding switch Journal Article
| Authors: | Huse, M.; Muir, T. W.; Xu, L.; Chen, Y. G.; Kuriyan, J.; Massagué, J. |
| Article Title: | The TGFβ receptor activation process: An inhibitor- to substrate-binding switch |
| Abstract: | The type I TGFβ receptor (TβR-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 TβR-I, prepared using protein semisynthesis. Phosphorylation of the GS region dramatically enhances the specificity of TβR-I for the critical C-terminal serines of Smad2. In addition, tetraphosphorylated TβR-I is bound specifically by Smad2 in a phosphorylation-dependent manner and is no longer recognized by the inhibitory protein FKBP12. Thus, phosphorylation activates TβR-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 TβR-I/Smad activation process. |
| Keywords: | protein expression; protein phosphorylation; unclassified drug; dna-binding proteins; nonhuman; cell cycle proteins; models, biological; smad2 protein; transforming growth factor beta; carboxy terminal sequence; protein; protein binding; enzyme activation; phosphorylation; amino acid sequence; molecular sequence data; amino terminal sequence; recombinant fusion proteins; protein synthesis; protein-serine-threonine kinases; immunoblotting; transforming growth factor beta receptor; transforming growth factor beta1; receptors, transforming growth factor beta; binding site; models, molecular; crystallography, x-ray; protein structure, tertiary; molecular structure; trans-activators; saccharomyces cerevisiae proteins; enzyme specificity; phosphothreonine; protein structure, secondary; receptor binding; phosphoserine; activin receptors, type i; article; protein fkbp12; tacrolimus binding protein 1a |
| Journal Title: | Molecular Cell |
| Volume: | 8 |
| Issue: | 3 |
| ISSN: | 1097-2765 |
| Publisher: | Cell Press |
| Date Published: | 2001-09-01 |
| Start Page: | 671 |
| End Page: | 682 |
| Language: | English |
| DOI: | 10.1016/s1097-2765(01)00332-x |
| PUBMED: | 11583628 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work