Identification of a binding site on the type II activin receptor for activin and inhibin

Type II activin receptors (ActRII and ActRIIB) are single-transmembrane dom ain serine/threonine kinase receptors that bind activin to initiate the sig naling and cellular responses triggered by this hormone, Inhibin also binds type II activin receptors and antagonizes many activin effects. Here we de scribe alanine scanning mutagenesis of the ActRII extracellular domain, We identify a cluster of three hydrophobic residues (Phe(42), Trp(60), and phe (83)) that, when individually mutated to alanine in the context of the full -length receptor, cause the disruption of activin and inhibin binding to Ac tRII, Each of the alanine-substituted ActRII mutants retaining activin bind ing maintains the ability to form crosslinked complexes with activin and su pports activin cross-linking to the type I activin receptor ALK4, Unlike wi ld-type ActRII, the three mutants unable to bind activin do not cause an in crease in activin signaling when transiently expressed in a corticotroph ce ll line, Together, our results implicate these residues in forming a critic al binding surface on ActRII required for functional interactions with both activin and inhibin, This first identification of a transforming growth fa ctor-p family member binding site may provide a general basis for character izing binding sites for other members of the superfamily.