Question

Would you expect fibronectin to have sugar modifications? Why or why not?

Answer 1

Sugar modifications of proteins are post-translational modifications, wherein there are attachments of carbohydrate groups to proteins via glycosidic bonds. These glycosidic bonds can be N-linked glycosylations or O-linked glycosylations.

Fibronectin (FN) is an extracellular matrix glycoprotein (ECM) involved in cell adhesion. They can bind to integrin receptors and form a bridge between extracellular matrix and the actin cytoskeleton. Hepatocytes secrete fibronectin in the plasma while cells such as fibroblasts, endothelial cells etc synthesize cellular fibronectin. It is known that plasma fibronectin contains several sites for N-linked glycosylation, which is required for cell adhesion. Homo-fibronectin has seven N-linked glycosylation sites and 1-2, O linked glycans. The carbohydrate residues in N-linked glycosylation of FN are mannose, galactose, glucosamine, and sialic acid. Classic receptor for fibronectin is alpha 5 beta 1 integrin. FN has also collagen and heparin binding domains as well as fibrin binding sites. N or O-linked glycosylation sites are mostly in within type III repeats and the collagen-binding domain of FN. These glycan are important to protect FN from undergoing hydrolysis by adopting a configuration that makes it poor substrate for proteolytic enzymes or by creating stearic hindrance for actions of these enzymes. This is required for collagen binding FN. Thus, if FN is lowly glycosylated, it is degraded by several proteases. They also help in modulation of binding affinity of FN to specific substrates. FN is required for wound healing in vivo.

Plasma FN glycosylation is important for cell adhesion and migration. These N-glycans mediate the interaction between the cell and fibronectin during wound healing. These Interactions will lead to generation of integrin mediated signaling. As a result, there will be fibroblast migration to the site of injury. If there are no N-glycans present on FN at specific sites, then cell attachment to FN will not occur. Hence, there is suppression of fibronectin-cell adhesion during wound healing.

Glycosylated cellular fibronectin levels are also increased during pregnancy complication such as preeclampsia. Glycosylated FN is used as a specific marker for detection of preterm labor in women, especially in cases of gestational diabetes. Oncofetal FN, formed in response to high glucose levels has O linked glycosylation. This o linked glycosylation is required for epithelial-mesenchymal transition that will eventually lead to tumors progression.

FN thus can undergo several sugar modifications. However, some may be required for normal cell migration processes, while other may not be beneficial and lead to diseased states.