(49g) Mathematical Modeling and Analysis of BMP-Receptor Complex Formation Elucidates Requirements for Heterodimer Dominant Signaling

Bone Morphogenetic Proteins (BMPs) play a pivotal role in developmental pattern formation and tissue homeostasis throughout the animal kingdom. A consistent feature in many examples of BMP signaling is the requirement for heterodimer ligands to elicit the highest signaling relative to their homodimer ligand counterparts. To investigate the biophysics of heterodimer dominance, we developed a mathematical model of receptor oligomeriztion and found that heterodimer ligands are not kinetically favored over other ligand-receptor combinations. With this as the starting point for analysis, we identified the minimal conditions needed in the model to confer heterodimer-dominant signaling and identified testable hypotheses for heterodimer dominance- 1) homodimer ligands are sequestered in the extracellular environment, 2) heterodimers have a modified kinetic rate that specifically enhances their interactions with receptors, and 3) receptor complexes formed by homodimers have weaker signaling. Testing the alternative explanations in vivo using zebrafish suggests that heterodimer dominance is conferred at the receptor complex formation stage and favors a mechanism where the heterodimers provide a compromise solution that overcomes the kinetic advantages of the stronger binding homodimer ligand.