TGF-beta is released from cells as a latent complex of three proteins: TGF-beta (which is encoded by three human genes), the processed TGF-beta propeptide (latency-associated peptide LAP), and a member of the latent TGF-beta binding protein (LTBP) family. LTBPs are microfibril (fibrillin)-associated proteins that bind LAP, tethering latent TGF-beta to microfibrils in the ECM (Taipale et al. 1996, Hyytiainen et al. 2004).
LTBP1 and LTBP4 incorporation into ECM requires fibrillin-1 (Ono et al. 2009). The protein–protein interaction sites between LTBPs and fibrillins have been determined using recombinant protein fragments and surface plasmon resonance (Ono et al. 2009). LTBP4 binds to the first hybrid domain of fibrillin-1 (Hyb1), whereas LTBP1 binds to a site involving both Hyb1 and adjacent EGF-like domains 2 and 3. Previous studies showed that the carboxyl terminus of LTBP1 binds to fibrillin-1, whereas the amino terminus of LTBPs is mainly responsible for binding ECM components made in cell culture generally, and fibronectin specifically (Kantola et al. 2008).