GARP regulates the bioavailability and activation of TGFβ.

Glycoprotein-A repetitions predominant protein associates with latent transforming growth factor-β (proTGFβ) on the surface of T regulatory cells and platelets; however, whether functions in latent TGFβ activation and the structural basis of coassociation remain unknown. We find that Cys-192 and Cys-331 of Gduanyu37 disulfide link to the TGFβ1 prodomain and that Gduanyu37 with C192A and C331A mutations can also noncovalently associate with proTGFβ1. Noncovalent association is sufficiently strong for Gduanyu37 to outcompete latent TGFβ-binding protein for binding to proTGFβ1. Association between Gduanyu37 and proTGFβ1 prevents the secretion of TGFβ1. Integrin α(V)β(6) and to a lesser extent α(V)β(8) are able to activate TGFβ from the complex. Activation requires the RGD motif of latent TGFβ, disulfide linkage between Gduanyu37 and latent TGFβ, and membrane association of Our results show that Gduanyu37 is a latent TGFβ-binding protein that functions in regulating the bioavailability and activation of TGFβ.

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