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

Abstract From sponges to mammals, TGFβ signalling is a central regulator of body plan, cell fate and tissue homeostasis, with receptor architecture highly conserved across metazoans. Here we identify unexpected evolutionary divergence within a key receptor structure: 12 independent ligand-binding domain (LBD) duplications across three receptor classes (ACVR1, BMPR2 and TGFBR2) in diverse vertebrate lineages, including fish, amphibians, birds, and mammals. These duplications reveal previously unrecognized structural and functional plasticity arising from domain-level innovation, including in established model organisms such as zebrafish, African clawed frog and chicken. Recently diverged lineages conserve the membrane-distal LBD and ligand-interacting residues, correlating with enhanced ligand binding, whereas more ancient lineages exhibit elevated evolutionary rates of the membrane-distal LBD associated with inhibitory function. Our findings reveal LBD multimerization as a recurring, lineage-independent mechanism that diversifies and fine-tunes TGFβ signalling, adding a regulatory dimension to one of the best-examined conserved and essential pathways in metazoan biology.