O-Mannosylation and human disease

Abstract

Glycosylation of proteins is arguably the most prevalent co- and post-translational modification. It is responsible for increased heterogeneity and functional diversity of proteins. Here we discuss the importance of one type of glycosylation, specifically O-mannosylation and its relationship to a number of human diseases. The most widely studied O-mannose modified protein is alpha-dystroglycan (α-DG). Recent studies have focused intensely on α-DG due to the severity of diseases associated with its improper glycosylation. O-mannosylation of α-DG is involved in cancer metastasis, arenavirus entry, and multiple forms of congenital muscular dystrophy [1, 2]. In this review, we discuss the structural and functional characteristics of O-mannose-initiated glycan structures on α-DG, enzymes involved in the O-mannosylation pathway, and the diseases that are a direct result of disruptions within this pathway.

Fig. 1

The dystrophin–glycoprotein complex. This multi-protein complex serves to anchor the extracellular matrix (ECM) to actin and other components of the cytoskeleton. O-mannosylated α-DG is a central component of this complex and serves as the binding partner for a number of extracellular matrix proteins (including laminin, perlecan, agrin, and neurexin) and also as a receptor for certain members of the Arenaviridae family of viruses. The interaction between α-DG and its binding partners is glycan-mediated and disruption is linked to a number of congenital muscular dystrophies and has also been implicated in tumor cell metastasis

Fig. 2

O-Mannose glycan structures. Classically, O-mannose is extended with GlcNAc in a β2-linkage. On α-DG this GlcNAc is typically seen further extended by galactose and sialic acid; the linkages and enzymes responsible for the additions are shown beside the glycans. However, the O-mannose of the laminin binding structure has been shown to be extended by GlcNAc in a novel β4-linkage and then further extended by GalNAc in a β3-linkage. The enzymes responsible for these additions have yet to be identified. The O-mannose of this structure is further modified by an unknown moiety, “X”, in a phosphodiester linkage to the 6 position of the mannose; this “X” modification is essential for laminin binding. The complete identity of “X” has not been solved but recent studies have suggested that LARGE is responsible for the addition of the repeating disaccharide, [-3Xyl-α1,3 GlcAβ1-] to this structure