BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-II

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Abstract
Bone morphogenetic protein‐2 (BMP‐2) induces bone formation and regeneration in adult vertebrates and regulates important developmental processes in all animals. BMP‐2 is a homodimeric cysteine knot protein that, as a member of the transforming growth factor‐β (TGF‐β) superfamily, signals by oligomerizing type I and type II receptor serine‐kinases in the cell membrane. The binding epitopes of BMP‐2 for BMPR‐IA (type I) and BMPR‐II or ActR‐II (type II) were characterized using BMP‐2 mutant proteins for analysis of interactions with receptor ectodomains. A large epitope 1 for high‐affinity BMPR‐IA binding was detected spanning the interface of the BMP‐2 dimer. A smaller epitope 2 for the low‐affinity binding of BMPR‐II was found to be assembled by determinants of a single monomer. Symmetry‐related pairs of the two juxtaposed epitopes occur near the BMP‐2 poles. Mutations in both epitopes yielded variants with reduced biological activity in C2C12 cells; however, only epitope 2 variants behaved as antagonists partially or completely inhibiting BMP‐2 activity. These findings provide a framework for the molecular description of receptor recognition and activation in the BMP/TGF‐β superfamily.