Binding Properties of the Transforming Growth Factor-β Coreceptor Betaglycan: Proposed Mechanism for Potentiation of Receptor Complex Assembly and Signaling

Transforming growth factor (TGF) beta 1, beta 2, and beta 3 (TGF-beta 1 TGF-beta 3, respectively) are small secreted signaling proteins that each signal through the TGF-beta type I and type II receptors (T beta RI and T beta RII, respectively). However, TGF-beta 2, which is well-known to bind TfiRII several hundred-fold more weakly than TGF-beta 1 and TGF-beta 3, has an additional requirement for betaglycan, a membrane-anchored nonsignaling receptor. Betaglycan has two domains that bind TGF-beta 2 at independent sites, but how it binds TGF-beta 2 to potentiate T beta RII binding and how the complex with TGF-beta, T beta RII, and betaglycan undergoes the transition to the signaling complex with TGF-beta 3 T beta RII, and T beta RI are not understood. To investigate the mechanism, the binding, of the TGF-beta s to the betaglycan extracellular domain, as well as its two independent binding domains, either directly or in combination with the TfiRI and TfiRII ectodomains, was studied using surface plasmon resonance, isothermal titration calorimetry, and size-exclusion chromatography. These studies show that betaglycan binds TGF-beta 3 homodimers with a 1:1 stoichiometry in a manner that allows one molecule of T beta RII to bind. These studies further show that betaglycan modestly potentiates the binding of T beta RII and must be displaced to allow T beta RI to bind. These findings suggest that betaglycan functions to bind and concentrate TGF-beta 2 on the cell surface and thus promote the binding of T beta RII by both membrane-localization effects and allostery. These studies further suggest that the transition to the signaling complex is mediated by the recruitment of TfiRI, which simultaneously displaces betaglycan and stabilizes the bound TfiRII by direct receptor receptor contact.