Structural and functional analysis of type I TGF-beta receptor regulation

摘要: The type I TGFβ receptor (TβR-I) is a transmembrane serine/threonine kinase of central importance to eukaryotic growth and homeostasis. TβR-I is activated by multiple phosphorylation of the GS region, a conserved juxtamembrane segment located just N-terminal to the protein kinase domain in the cytoplasmic portion of the receptor. In this thesis, I describe structural and biochemical studies aimed at understanding the molecular basis of TβR-I regulation by the GS region. The crystal structure of the unphosphorylated cytoplasmic portion of TβR-I containing both the GS region and the catalytic domain, has been determined in complex with the FK506-binding protein FKBP12, which binds to the GS region an inhibits TGFβ signaling.(TβR-I) adopts a catalytically inactive conformation in this structure that is maintained, in part, by the unphosphorylated GS region. FKBP12 binds to the GS region, capping the activating …