O-linked glycosylation

O-N-acetylgalactosamine (O-GalNAc) Addition of N-acetylgalactosamine (GalNAc) to a serine or threonine occurs in the Golgi apparatus, after the protein has been folded. The process is performed by enzymes known as GalNAc transferases (GALNTs), of which there are 20 different types. However, there are often proline (Pro) residues near the threonine or serine. Mucins are a group of heavily O-glycosylated proteins that line the gastrointestinal and respiratory tracts to protect these regions from infection. O-N-acetylglucosamine (O-GlcNAc) Addition of N-acetylglucosamine (O-GlcNAc) to serine and threonine residues usually occurs on cytoplasmic and nuclear proteins that remain in the cell, compared to O-GalNAc modifications which usually occur on proteins that will be secreted. O-GlcNAc modifications were only recently discovered, but the number of proteins with known O-GlcNAc modifications is increasing rapidly. Because O-GlcNAc can be added and removed, it is known as a dynamic modification and has a lot of similarities to phosphorylation. O-GlcNAcylation and phosphorylation can occur on the same threonine and serine residues, suggesting a complex relationship between these modifications that can affect many functions of the cell. The modification affects processes like the cells response to cellular stress, the cell cycle, protein stability and protein turnover. It may be implicated in neurodegenerative diseases like Parkinson's and late-onset Alzheimer's and has been found to play a role in diabetes. Because both O-GlcNAcylation and phosphorylation can affect specific residues and therefore both have important functions in regulating signalling pathways, both of these processes provide interesting targets for cancer therapy. O-Mannose (O-Man) O-mannosylation involves the transfer of a mannose from a dolichol-P-mannose donor molecule onto the serine or threonine residue of a protein. Most other O-glycosylation processes use a sugar nucleotide as a donor molecule. The best characterised O-mannosylated human protein is α-dystroglycan. Ribitol, xylose and glucuronic acid can be added to this structure in a complex modification that forms a long sugar chain. While this O-galactosylation is necessary for correct function in all collagens, it is especially common in collagen types IV and V. In some cases, a glucose sugar can be added to the core galactose. These were discovered in Plasmodium falciparum and Toxoplasma gondii. Several different enzymes catalyse the elongation of the core fucose, meaning that different sugars can be added to the initial fucose on the protein. Changes in the elaboration of the core fucose determine what interactions the protein can form, and therefore which genes will be transcribed during development. O-fucosylation might also play a role in protein breakdown in the liver. ==Proteoglycans==

Proteoglycans consist of a protein with one or more sugar side chains, known as glycosaminoglycans (GAGs), attached to the oxygen of serine and threonine residues. GAGs consist of long chains of repeating sugar units. Proteoglycans are usually found on the cell surface and in the extracellular matrix (ECM), and are important for the strength and flexibility of cartilage and tendons. Absence of proteoglycans is associated with heart and respiratory failure, defects in skeletal development and increased tumor metastasis. Different types of proteoglycans exist, depending on the sugar that is linked to the oxygen atom of the residue in the protein. For example, the GAG heparan sulphate is attached to a protein serine residue through a xylose sugar. The structure is extended with several N-acetyllactosamine repeating sugar units added onto the xylose. This process is unusual and requires specific xylosyltransferases. Keratan sulphate attaches to a serine or threonine residue through GalNAc, and is extended with two galactose sugars, followed by repeating units of glucuronic acid (GlcA) and GlcNAc. Type II keratan sulphate is especially common in cartilage. ==Lipids==

Galactose or glucose sugars can be attached to a hydroxyl group of ceramide lipids in a different form of O-glycosylation, as it does not occur on proteins. This forms glycosphingolipids, which are important for the localisation of receptors in membranes. Incorrect breakdown of these lipids leads to a group of diseases known as sphingolipidoses, which are often characterised by neurodegeneration and developmental disabilities. Because both galactose and glucose sugars can be added to the ceramide lipid, we have two groups of glycosphingolipids. Galactosphingolipids are generally very simple in structure and the core galactose is not usually modified. Glucosphingolipids, however, are often modified and can become a lot more complex. Biosynthesis of galacto- and glucosphingolipids occurs differently. Glucose is added onto ceramide from its precursor in the endoplasmic reticulum, before further modifications occur in the Golgi apparatus. Galactose, on the other hand, is added to ceramide already in the Golgi apparatus, where the galactosphingolipid formed is often sulfated by addition of sulfate groups. ==Glycogenin==

One of the first and only examples of O-glycosylation on tyrosine, rather than on serine or threonine residues, is the addition of glucose to a tyrosine residue in glycogenin. ==Clinical significance==

All forms of O-glycosylation are abundant throughout the body and play important roles in many cellular functions. Lewis epitopes are important in determining blood groups, and allow the generation of an immune response if we detect foreign organs. Understanding them is important in organ transplants. Hinge regions of immunoglobulins contain highly O-glycosylated regions between individual domains to maintain their structure, allow interactions with foreign antigens and protect the region from proteolytic cleavage. Alzheimer's may be affected by O-glycosylation. Tau, the protein that accumulates to cause neurodegeneration in Alzheimer's, contains O-GlcNAc modifications which may be implicated in disease progression. Changes in O-glycosylation are extremely common in cancer. O-glycan structures, and especially the terminal Lewis epitopes, are important in allowing tumor cells to invade new tissues during metastasis. Understanding these changes in O-glycosylation of cancer cells can lead to new diagnostic approaches and therapeutic opportunities. == See also ==