Crystal Structure of the Cytoplasmic Domain of the Type I TGF β Receptor in Complex with FKBP12

Abstract

Activation of the type I TGF β receptor (T β R-I) requires phosphorylation of a regulatory segment known as the GS region, located upstream of the serine/threonine kinase domain in the cytoplasmic portion of the receptor. The crystal structure of a fragment of unphosphorylated T β R-I, containing both the GS region and the catalytic domain, has been determined in complex with the FK506-binding protein FKBP12. T β R-I adopts an inactive conformation that is maintained by the unphosphorylated GS region. FKBP12 binds to the GS region of the receptor, capping the T β R-II phosphorylation sites and further stabilizing the inactive conformation of T β R-I. Certain structural features at the catalytic center of T β R-I are characteristic of tyrosine kinases rather than Ser/Thr kinases.