Independent multimerization of Latent TGFβ Binding Protein-1 stabilized by cross-linking and enhanced by heparan sulfate

TGF beta plays key roles in fibrosis and cancer progression, and latency is conferred by covalent linkage to latent TGF beta binding proteins (LTBPs). LTBP1 is essential for TGF beta folding, secretion, matrix localization and activation but little is known about its structure due to its inherent size and flexibility. Here we show that LTBP1 adopts an extended conformation with stable matrix-binding N-terminus, extended central array of 11 calcium-binding EGF domains and flexible TGF beta-binding C-terminus. Moreover we demonstrate that LTBP1 forms short filament-like structures independent of other matrix components. The termini bind to each other to facilitate linear extension of the filament, while the N-terminal region can serve as a branch-point. Multimerization is enhanced in the presence of heparin and stabilized by the matrix cross-linking enzyme transglutaminase-2. These assemblies will extend the span of LTBP1 to potentially allow simultaneous N-terminal matrix and C-terminal fibrillin interactions providing tethering for TGF beta activation by mechanical force.