ABSTRACT
Transforming growth factor-ß1, -ß2, and -ß3 (TGF-ß1, -ß2, and -ß3) are secreted signaling ligands that play essential roles in tissue development, tissue maintenance, immune response, and wound healing. TGF-ß ligands form homodimers and signal by assembling a heterotetrameric receptor complex comprised of two type I receptor (TßRI):type II receptor (TßRII) pairs. TGF-ß1 and TGF-ß3 ligands signal with high potency due to their high affinity for TßRII, which engenders high-affinity binding of TßRI through a composite TGF-ß:TßRII binding interface. However, TGF-ß2 binds TßRII 200-500 more weakly than TGF-ß1 and TGF-ß3 and signals with lower potency compared with these ligands. Remarkably, the presence of an additional membrane-bound coreceptor, known as betaglycan, increases TGF-ß2 signaling potency to levels similar to TGF-ß1 and -ß3. The mediating effect of betaglycan occurs even though it is displaced from and not present in the heterotetrameric receptor complex through which TGF-ß2 signals. Published biophysics studies have experimentally established the kinetic rates of the individual ligand-receptor and receptor-receptor interactions that initiate heterotetrameric receptor complex assembly and signaling in the TGF-ß system; however, current experimental approaches are not able to directly measure kinetic rates for the intermediate and latter steps of assembly. To characterize these steps in the TGF-ß system and determine the mechanism of betaglycan in the potentiation of TGF-ß2 signaling, we developed deterministic computational models with different modes of betaglycan binding and varying cooperativity between receptor subtypes. The models identified conditions for selective enhancement of TGF-ß2 signaling. The models provide support for additional receptor binding cooperativity that has been hypothesized but not evaluated in the literature. The models further showed that betaglycan binding to the TGF-ß2 ligand through two domains provides an effective mechanism for transfer to the signaling receptors that has been tuned to efficiently promote assembly of the TGF-ß2(TßRII)2(TßRI)2 signaling complex.
