Model Structure of Decorin and Implications for Collagen Fibrillogenesis

Abstract

The three-dimensional structure of human decorin, a secreted proteoglycan involved in the regulation of collagen fibrillogenesis and cellular growth, has been modeled based on the crystal structure of the porcine ribonuclease inhibitor. Both proteins contain leucine-rich repeats and share 18% identical residues. This model structure of decorin has an arch shape with the single glycosaminoglycan chain and the three N-linked oligosaccharides located on the same side of the molecule. Decorin was modeled as binding to a polar sequence of collagen type I found in the d band. The inner concave surface is the appropriate size and shape to accommodate only one collagen triple helix of approximately 3 nm in length. The binding of one collagen triple helix to decorin is proposed to play a major role in the formation of the staggered arrangement of collagen molecules within the microfibrils by preventing lateral fusion of collagen molecules.

Decorin suppresses tumor cell-mediated angiogenesis

“…In our studies, we used both co-culture and tumor cell-conditioned media and found a consistent retardation of HUVEC migration, attachment, and differentiation with either decorin-expressing cells or decorin-containing media. Our results suggest that decorin does not have a direct effect on these processes unlike that of ribonuclease inhibitor (Polakowski et al, 1993), a leucine-rich protein with a threedimensional structure similar (Kobe and Deisenhofer, 1993) to that proposed for decorin (Weber et al, 1996). Specifically, ribonuclease inhibitor causes a significant reduction in tumor growth of C755 mammary tumor xenografts via a direct inhibition of tumor-induced neovascularization (Polakowski et al, 1993).…”

Lumican, a small leucine‐rich proteoglycan

“…However, it appears that not all of the sites can serve as acceptors for KS synthesis, and in the chick cornea only three of the four sites are so substituted (29). Rotary-shadowing electronic microscopy of the archetypal SLRP member decorin demonstrated an open arch-shaped structure (30), which was recently confirmed by crystallographic analysis (31). Molecular modeling further demonstrated that it is possible to build horseshoe-shaped structures for all the members of the SLRP superfamily (32).…”

“…Molecular modeling further demonstrated that it is possible to build horseshoe-shaped structures for all the members of the SLRP superfamily (32). The horseshoe structure is envisioned with the glycosaminoglycan (GAG) chains protruding from the convex surface, whereas the concave surface is free to bind parallel collagen microfibrils and regulate their lateral association (30). Dimerization of the arch-shaped SLRP structure in solution has also been proposed (31).…”

“…The unique LRR structure enables lumican to interact with fibrillar collagens and thus to modulate fibril formation while highly charged GAG chains extend out to regulate interfibrillar spacings (30). In vivo lumican has been found to colocalize with collagens in skin, tendon, muscle connective tissue, and the cornea of the eye (28).…”

Decorin Binds to a Narrow Region of the Epidermal Growth Factor (EGF) Receptor, Partially Overlapping but Distinct from the EGF-binding Epitope

“…the central LRR 6 is required for proper interaction with the EGFR. This is notable because a similar region has been involved in the binding to collagen (49 -51) and transforming growth factor-␤ (52), further stressing that this region, which lines the apex of the arch-shaped decorin (9), is directly responsible for the active binding of various ligands with no obvious structural similarities. Indeed, this region is enriched in charged amino acid residues (Fig.…”