Structural Basis for Integrin-Independent Activity of Latent TGF-β3 9072

Abstract Description The transforming growth factor-beta (TGF-β) family, including TGF-β1, TGF-β2, and TGF-β3, is synthesized as pro-peptides with a latency-associated protein (LAP) and a receptor binding domain. These pro-peptides are processed into latent complexes that, for TGF-β1, can not engage TGFβ receptors unless activated. Latent TGF-β1 requires integrin-dependent activation, whereas latent TGF-β3 exhibits intrinsic activity via an integrin-independent mechanism with lower activation thresholds. The mechanistic basis for latent TGF-β3 activity remains unclear. We demonstrate that a specific motif in the LAP of TGF-β1, absent in the LAP of TGF-β3, suppresses the integrin-independent activity of TGF-β3. This activity can be restored through integrin-dependent mechanisms, mimicking regulation seen in TGF-β1. Latent TGF-β3 strongly associates with its high-affinity receptor TGFβR2, leading to effective downstream signaling and collagen deposition in fibroblasts. Using CryoEM, we resolved the structure of latent TGF-β3, revealing a dynamic interaction between the LAP and the receptor binding domain that explains its activity. Substituting a minimal LAP motif from TGF-β1 into TGF-β3 enforces more stringent regulation of the receptor binding domain, highlighting previously uncharacterized conformational differences between TGF-β isoforms. This study elucidates structural and functional nuances that distinguish TGF-β isoforms, providing insights into their distinct regulatory mechanisms. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)