Structural insights into BMP receptors: Specificity, activation and inhibition

• TGFβ ligands fall into four functionally distinct subgroups differing in receptor activation and signaling modulation.
• A large number of TGFβ/BMP ligands signal though a limited set of receptor.
• Numeral ligand–receptor discrepancy leads to promiscuous receptor usage.
• Mechanisms have evolved to facilitate not only correct ligand-type I receptor pairing but also strict type I receptor-Smad pairing ensuring activation of only one particular SMAD branch.
• Structures of TGFβ/BMP receptor kinases enable the design of specific kinase inhibitors.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β family (TGFβ), which signal through hetero-tetrameric complexes of type I and type II receptors. In humans there are many more TGFβ ligands than receptors, leading to the question of how particular ligands can initiate specific signaling responses. Here we review structural features of the ligands and receptors that contribute to this specificity. Ligand activity is determined by receptor–ligand interactions, growth factor prodomains, extracellular modulator proteins, receptor assembly and phosphorylation of intracellular signaling proteins, including Smad transcription factors. Detailed knowledge about the receptors has enabled the development of BMP-specific type I receptor kinase inhibitors. In future these may help to treat human diseases such as fibrodysplasia ossificans progressiva.

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