Abstract:
:Bone morphogenetic proteins (BMP) are dimeric factors initiating several distinct signaling cascades by binding to two types of transmembrane serine/threonine kinase receptors (BRI and BRII), and are thus regulating several steps in embryonal development and adult tissue homeostasis. BMP-2 contains two symmetrical pairs of juxtaposed epitopes: the wrist epitope with high affinity to BRI consists of residues from both BMP-2 monomers, while the knuckle epitope resembles the low affinity site for BRII and comprises residues from only one monomer. Here we generated heterodimeric BMP-2 muteins with 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-). These muteins (B2eI-/B2m- and B2eII-/B2m-) were analyzed by biosensor analysis as well as by measuring their biological activity and compared to their homodimeric forms (either wild type or mutant). Depletion of only one epitope II results in the loss of biological activity as measured byalkaline phosphatase (ALP) activity and Smad induced reportergene assays. However, depletion of only one epitope I shows a reduction of ALP activity to about 25%, while the activation of the Smad pathway remained normal. Homomeric muteins are non-functional for both Smad and ALP activation. This suggests that two functional epitopes II have to be present on one BMP-2 molecule for receptor activation. Futhermore, both pathways (Smad and ALP) are triggered differently by distinct BMP-receptor complexes. Heteromeric BMP-2 mutants therefore allow a distinguishable manipulation of either pathway and thus represent important tools for the generation of specific BMP-2 antagonists or agonists.
journal_name
Biol Chemjournal_title
Biological chemistryauthors
Knaus P,Sebald Wdoi
10.1515/BC.2001.149keywords:
subject
Has Abstractpub_date
2001-08-01 00:00:00pages
1189-95issue
8eissn
1431-6730issn
1437-4315journal_volume
382pub_type
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