Latent transforming growth factor -binding protein 1 (LTBP-1) targets latent complexes of transforming growth factor  to the extracellular matrix, where the latent cytokine is subsequently activated by several different mechanisms. Fibrillins are extracellular matrix macromolecules whose primary function is architectural: fibrillins assemble into ultrastructurally distinct microfibrils that are ubiquitous in the connective tissue space. LTBPs and fibrillins are highly homologous molecules, and colocalization in the matrix of cultured cells has been reported. To address whether LTBP-1 functions architecturally like fibrillins, microfibrils were extracted from tissues and analyzed immunochemically. In addition, binding studies were conducted to determine whether LTBP-1 interacts with fibrillins. LTBP-1 was not detected in extracted beaded-string microfibrils, suggesting that LTBP-1 is not an integral structural component of microfibrils. However, binding studies demonstrated interactions between LTBP-1 and fibrillins. The binding site was within three domains of the LTBP-1 C terminus, and in fibrillin-1 the site was defined within four domains near the N terminus. Immunolocalization data were consistent with the hypothesis that LTBP-1 is a fibrillin-associated protein present in certain tissues but not in others. In tissues where LTBP-1 is not expressed, LTBP-4 may substitute for LTBP-1, because the C-terminal end of LTBP-4 binds equally well to fibrillin. A model depicting the relationship between LTBP-1 and fibrillin microfibrils is proposed.The fibrillins and latent transforming growth factor -binding proteins (LTBPs) 1 are members of a family of homologous molecules. The fibrillins and LTBPs contain multiple calciumbinding epidermal growth factor-like modules interspersed by a domain module (the 8-Cys or TB module), so far found only in these two proteins. Fibrillin-1 (1-4) and fibrillin-2 (5, 6) share a highly similar overall structure. Both molecules are of equivalent size (ϳ350 kDa) and domain organization. In contrast, LTBP-1 (7, 8), LTBP-2 (9), LTBP-3 (10), and LTBP-4 (11, 12) are each smaller than the fibrillins and variable in size.Extensive immunolocalization data combined with structural analyses of the fibrillin-1 monomer and fibrillin-containing microfibrils (1, 13-15) have established that fibrillin-1 is a major structural component of connective tissue microfibrils. In addition, genetic evidence in humans (16, 17) and mice (18,19) has confirmed that fibrillin-1 performs a significant role in the maintenance of microfibrils and elastic fibers.Fibrillin-2, whose structure is predicted to be highly similar to fibrillin-1, has also been immunolocalized to microfibrils (20). However, in contrast to fibrillin-1, the contribution of fibrillin-2 to microfibril structure is temporally and spatially restricted. In situ hybridization studies in mice indicated that expression of the fbn2 gene is most prominent in the early developing fetus (20). Genetic evidence in humans (5, 21) suggests that fibrillin-...
Latent transforming growth factor (TGF)Results demonstrate that these protein-protein interactions exhibit "exquisite specificities," a phrase commonly used to describe monoclonal antibody interactions. Despite these differences, interactions between LTBP-1 and fibrillin-1 compete for interactions between fibrillin-1 and these fibulins. All of these proteins have been immunolocalized to microfibrils. However, in fibrillin-1 (Fbn1) null fibroblast cultures, LTBP-1 and LTBP-4 are not incorporated into microfibrils. In contrast, in fibulin-2 (Fbln2) null or fibulin-4 (Fbln4) null cultures, fibrillin-1, LTBP-1, and LTBP-4 are incorporated into microfibrils. These data show for the first time that fibrillin-1, but not fibulin-2 or fibulin-4, is required for appropriate matrix assembly of LTBPs. These studies also suggest that the fibulins may affect matrix sequestration of LTBPs, because in vitro interactions between these proteins are competitive.
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