title: The TGF beta receptor activation process: an inhibitor- to substrate-binding switch.
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.
authors.affiliation: Laboratory of Molecular Biophysics, Rockefeller University, New York, NY 10021, USA.
authors.forename: M
authors.initials: M
authors.lastname: Huse
authors.forename: T W
authors.initials: TW
authors.lastname: Muir
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.forename: Y G
authors.initials: YG
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Kuriyan
authors.forename: J
authors.initials: J
authors.lastname: Massagué
mesh_terms: D030201:Activin Receptors, Type I; D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D051899:Smad2 Protein; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D051899:Smad2 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D064447:Checkpoint Kinase 2; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C067022:RAD53 protein, S cerevisiae; D022061:Tacrolimus Binding Protein 1A