A Novel Functional Role of Collagen Glycosylation

Abstract

Collagens make up the most abundant component of interstitial extracellular matrices and basement membranes. Collagen remodeling is a crucial process in many normal physiological events and in several pathological conditions. Some collagen subtypes contain specific carbohydrate side chains, the function of which is poorly known. The endocytic collagen receptor urokinase plasminogen activator receptor-associated protein (uPARAP)/Endo180 plays an important role in matrix remodeling through its ability to internalize collagen for lysosomal degradation. uPARAP/Endo180 is a member of the mannose receptor protein family. These proteins all include a fibronectin type II domain and a series of C-type lectin-like domains, of which only a minor part possess carbohydrate recognition activity. At least two of the family members, uPARAP/Endo180 and the mannose receptor, interact with collagens. The molecular basis for this interaction is known to involve the fibronectin type II domain but nothing is known about the function of the lectin domains in this respect. In this study, we have investigated a possible role of the single active lectin domain of uPARAP/ Endo180 in the interaction with collagens. By expressing truncated recombinant uPARAP/Endo180 proteins and analyzing their interaction with collagens with high and low levels of glycosylation we demonstrated that this lectin domain interacts directly with glycosylated collagens. This interaction is functionally important because it was found to modulate the endocytic efficiency of the receptor toward highly glycosylated collagens such as basement membrane collagen IV. Surprisingly, this property was not shared by the mannose receptor, which internalized glycosylated collagens independently of its lectin function. This role of modulating its uptake efficiency by a specific receptor is a previously unrecognized function of collagen glycosylation.The breakdown and remodeling of the extracellular matrix (ECM) 2 including the basement membrane are important steps in embryonic growth, tissue rearrangements in the healthy body, and invasive cancer growth (1-3). The ECM is composed of a range of different structural proteins, including collagens, laminins, fibronectin, and proteoglycans. The collagens make up by far the most abundant component. Collagens are trimeric proteins that form unique triple helices and assemble into large supramolecular structures such as fibers and sheets, enabling them to form the barriers and structures of the ECM (4).Collagens undergo a range of post-translational modifications, including extensive hydroxylation of prolyl and lysyl residues, N-and O-linked glycosylation, and processing of proforms (5). The hydroxylation of proline and lysine residues plays a role in triple helix stabilization and cross-linking of collagen molecules and the processing of proforms is important for the assembly of collagens into fibrillar structures (6). In contrast, the role of collagen glycosylation is poorly understood. Most is known about the O-linked glycosylation...

Galectin-3 Enhances Epithelial Cell Adhesion and Wound Healing in Rat Cornea

“…Human limbal epithelial cells are partially enriched by adhesion to collagen IV [12], and collagen IV promotes adhesion and motility of human corneal epithelial cells not observed with laminin and fibronectin [27]. Collagen IV contains a high level of hydroxylysine important for the attachment of carbohydrates such as galactose and N-acetylglucosamine to the carbohydrate recognition domain of galectin-3 [28,29,30,31]. Thus, corneal epithelial cell adhesion on collagen IV may be important for corneal wound healing.…”

Collagen Type I as a Ligand for Receptor-Mediated Signaling

“…This mesenchymal cell surface receptor has an important function in collagen internalization [38][39][40]. In addition, uPARAP/Endo180 was shown to aid in the initial adhesion of fibroblasts to collagen and to accelerate the migration of these cells on a fibrillar collagen matrix [38,39,41,42]. In bone, this receptor is highly expressed on osteoblasts and osteocytes at sites of endochondral and intramembranous ossification during development [38].…”

“…Characteristically this family of proteins includes an N-terminal, cysteine-rich/ricin B like domain, a fibronectin type II domain, and a series of 8-10 C-type lectin-like domains. This mesenchymal cell surface receptor has an important function in collagen internalization [38][39][40]. In addition, uPARAP/Endo180 was shown to aid in the initial adhesion of fibroblasts to collagen and to accelerate the migration of these cells on a fibrillar collagen matrix [38,39,41,42].…”

Carbohydrate, Biomaterials, and Tissue Engineering Applications

“…Moreover, carbohydrate structures encode information that modulates interactions between cells and the extracellular matrix (ECM) [13,14]. On the basis of these premises, saccharidic motifs are undoubtedly interesting cues to be used for the upgrading of synthetic or natural polymers to smart biomaterials with the ability to cross-talk with their biological environment.…”