Recurrent evolution of ligand-binding domain multiplicity fine-tunes TGFβ signaling in vertebrates

From sponges to mammals, TGFβ-signaling has evolved as one of the key pathways governing body plans, organ and cell type differentiations as well as homeostatic balance. The extensive conservation of the receptor core architecture across metazoans reflects strong evolutionary constraints, consistent with the severe developmental phenotypes caused by TGFβ receptor mutations in humans. Here, we identify unexpected evolutionary divergence within a key receptor structure: 12 independent multiplications of the ligand-binding domain across three receptor classes (ACVR1, BMPR2, TGFBR2) in a diverse set of vertebrate lineages, including fish, amphibians, birds, and mammals. These ligand binding domain duplications indicate structural and functional plasticity of TGFβ receptors arising from domain-level innovation, a feature that has remained unnoticed in established model organisms including zebrafish, the African clawed frog, and chicken. Two principal effects emerged. First, recently diverged lineages display strong conservation of the membrane-proximal ligand binding domain (LBD) relative to the membrane-distal LBD, including the ligand-interacting residues. In species such as chicken and salmon, this pattern is associated with enhanced ligand binding. Second, more ancient lineages, such as zebrafish, exhibit elevated evolutionary rates in the membrane-distal LBD, corresponding to the acquisition of an inhibitory function. Our findings reveal LBD multimerization as a recurring, lineage-independent broader mechanism to diversify or fine-tune TGFβ-signaling. This adds a novel regulatory dimension to one of the best-examined conserved and essential pathways in metazoan biology.