Model of fibrillin-1 containing microfibrils showing the locations of binding sites for ADAMTSL proteins, LTBP-1, and integrins.

This model of fibrillin-1 molecules arranged as parallel, staggered molecules within the beads-on-a-string microfibril was previously proposed [33]. Two staggered fibrillin-1 molecules are shown with colored domains (see Figure 1c for domain structure), while other fibrillin molecules within the microfibril are depicted as dashed black lines. Beaded regions of the microfibril are represented as gray scalloped circles. The inset shows the N-terminus (black) of one molecule extending through cbEGF5 and crossing over the middle portion of a second molecule (shown from Hybrid2 through cbEGF27). In this model, binding sites for ADAMTSL proteins (within the first 8-cysteine domain, the proline-rich domain, and the adjacent generic EGF-like domain) and for LTBP-1 (within the first hybrid domain) on one molecule are very close to the integrin-binding RGD site (contained in the fourth 8-cysteine domain) on a second molecule. Mutations in the fourth 8-cysteine domain can cause SSKS, presumably by disrupting integrin binding. The fifth 8-cysteine domain or TB5 contains mutations in FBN1 that result in WMS [3], geleophysic (GD) or acromicric dysplasia (AD) [34]. Mutations in ADAMTSL2 also lead to GD, and mutations in ADAMTS10 lead to WMS. We propose that this cluster of molecular interactions (magnified in the inset) constitutes a microenvironment controlling thick skin and musculoskeletal growth.