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Bone morphogenetic proteins (BMP) are dimeric factorsinitiating several distinct signaling cascades by binding to two types oftransmembrane serine/threonine kinase receptors (BRI and BRII), and are thusregulating several steps in embryonal development and adult tissue homeostasis.BMP-2 contains two symmetrical pairs of juxtaposed epitopes: the wrist epitopewith high affinity to BRI consists of residues from both BMP-2 monomers, whilethe knuckle epitope resembles the low affinity site for BRII and comprisesresidues from only one monomer. Here we generated heterodimeric BMP-2 muteinswith one monomer mutant in either epitope I for BRI (eI) or epitope II for BRII(eII) and the second monomer wild type for receptor interactions (m). Thesemuteins (B2eI/B2m and B2eII/B2m) were analyzed by biosensor analysis as well asby measuring their biological activity and compared to their homodimeric forms(either wild type or mutant). Depletion of only one epitope II results in theloss of biological activity as measured by alkaline phosphatase (ALP) activityand Smad induced reportergene assays. However, depletion of only one epitope Ishows a reduction of ALP activity to about 25%, while the activation of theSmad pathway remained normal. Homomeric muteins are nonfunctional for both Smadand ALP activation. This suggests that two functional epitopes II have to bepresent on one BMP-2 molecule for receptor activation. Futhermore, bothpathways (Smad and ALP) are triggered differently by distinct BMPreceptorcomplexes. Heteromeric BMP-2 mutants therefore allow a distinguishablemanipulation of either pathway and thus represent important tools for thegeneration of specific BMP-2 antagonists or agonists.

Cooperativity of Binding Epitopes and Receptor Chains in the BMP/TGFß Superfamily