Antagonism of activin by activin chimeras.

Activins are pluripotent hormones/growth factors that belong to the TGF-β superfamily of growth and differentiation factors (GDFs). They play a role in cell growth, differentiation and apoptosis, endocrine function, metabolism, wound repair, immune responses, homeostasis, mesoderm induction, bone growth, and many other biological processes. Activins and the related bone morphogenic proteins (BMPs) transduce their signal through two classes of single transmembrane receptors. The receptors possess intracellular serine/threonine kinase domains. Signaling occurs when the constitutively active type II kinase domain phosphorylates the type I receptor, which upon activation, phosphorylates intracellular signaling molecules. To generate antagonistic ligands, we generated chimeric molecules that disrupt the receptor interactions and thereby the phosphorylation events. The chimeras were designed based on available structural data to maintain high-affinity binding to type II receptors. The predicted type I receptor interaction region was replaced by residues present in inactive homologs or in related ligands with different type I receptor affinities.