O-Glycosylation of the Mucin Type

Abstract

While only about ten percent of the databank entries are defined as glycoproteins, it has been estimated recently that more than half of all proteins are glycoproteins. Mucin-type O-glycosylation is a widespread post-translational modification of proteins found in the entire animal kingdom, but also in higher plants. The structural complexity of the chains initiated by O-linked GalNAc exceeds that of N-linked chains by far. The process during which serine and threonine residues of proteins become modified is confined to the cis to trans Golgi compartments. The initiation of this process by peptidyl GalNAc-transferases is ruled by the sequence context of putative O-glycosylation sites, but also by epigenetic regulatory mechanisms, which can be mediated by enzyme competition. The cellular repertoir of glycosyltransferases with their distinct donor sugar and acceptor sugar specificities, their sequential action at highly-ordered surfaces, and their localizations in subcompartments of the Golgi finally determine the cell-specific O-glycosylation profile. Dramatic alterations of the glycosylation machinery are observed in cancer cells, resulting in aberrantly O-glycosylated proteins that expose previously masked peptide motifs and new antigenic targets. The functional aspects of O-linked glycans, which comprise among many others their potential role in sorting and secretion of glycoproteins, their influence on protein conformation, and their multifarious involvement in cell adhesion and immunological processes, appear as complex as their structures.

Requirement for a core 1 galactosyltransferase in the Drosophila nervous system

“…One common class of O-linked glycosylation in eukaryotes encompasses glycans attached to extracellular protein domains by means of an O-linked N-acetylgalactosamine (O-GalNAc; Hanisch, 2001;Hang and Bertozzi, 2005). This is commonly referred to as mucin-type glycosylation, because of its association with heavily glycosylated mucin proteins.…”

“…In this context, mucin-type glycosylation is thought to form a protective barrier and extracellular lubricant. However, mucin-type glycosylation is also found on a wide variety of other proteins, and implicated in diverse functions, from lymphocyte homing to sperm-egg binding (Hanisch, 2001;Hang and Bertozzi, 2005). Additionally, aberrant mucintype glycosylation is also often associated with tumor metastasis (Brooks et al, 2008).…”

“…Several alternate core structures, in which different sugars are attached to O-GalNAc, have also been described, and the core O-linked glycans can then be elongated in diverse ways to generate a wide variety of mucin-type glycans (Hanisch, 2001;Hang and Bertozzi, 2005). The Dro-sophila genome does not appear to encode homologues of many of the enzymes required for the generation of the complex and diverse mucin-type glycans found in vertebrates (Adams et al, 2000), and mass spectrometry of O-glycans in Drosophila embryos identified mostly disaccharide (T antigen; North et al, 2006;Aoki et al, 2008).…”

Thrombocytopenia and kidney disease in mice with a mutation in the C1galt1 gene

“…C1GalT1 generates the core1 disaccharide O-glycan Gal␤1-3GalNAc␣1-Ser͞Thr, also known as the T antigen, by addition of Gal to GalNAc␣1-Ser͞Thr (the Tn antigen), which is initially generated by the action of Nacetylgalactosaminyltransferases on specific Ser or Thr residues of target proteins. The core1 disaccharide is the precursor for the synthesis of many of the extended mucin-type O-glycans found on mammalian glycoproteins (6). Compromised C1GalT1 activity has been associated with disease in humans, most notably Tn syndrome, a rare hematological disorder characterized by reduced numbers of blood cells (7), and IgA nephropathy, a common primary glomerulonephritis (8).…”

The Tat-conjugated N-terminal region of mucin antigen 1 (MUC1) induces protective immunity against MUC1-expressing tumours

“…Because the VNTR is enriched with serine and threonine residues that are attached by O-linked glycans, MUC1 is hyperglycosylated in normal cells [1]. In various cancers, such as breast, ovary, lung, pancreas and prostate tumours, MUC1 is increased more than 100-fold and aberrantly underglycosylated [2].…”