Glycosylation

From Academic Kids

Glycosylation is the process or result of addition of saccharides to proteins and lipids. The process is one of four principal post-translational modification steps in the synthesis of membrane and secreted proteins and the majority of proteins synthesized in the rough ER undergo glycosylation. It is an enzyme-directed site-specific process, as opposed to the non-ezymatic chemical reaction of glycation. There exists N-linked glycosylation to the amide nitrogen of asparagine side chains and O-linked glycosylation to the hydroxy oxygen of serine and threonine side chains.

Contents

Purpose

The polysaccharide chains attached to the target proteins serve various functions. For instance, some proteins do not fold correctly unless they are glycosylated first. Also, polysaccharides linked at the amide nitrogen of asparagine in the protein confer stability on some secreted glycoproteins. Experiments have shown that glycosylation in this case is not a strict requirement for proper folding, but the unglycosylated protein degrades quickly. Glycosylation may play a role in cell-cell adhesion (a mechanism employed by cells of the immune system) as well.

Mechanisms

There are various mechanisms for glycosylation, although all share several common features.

  • Glycosylation is an enzymatic process
  • The donor molecule is an activated nucleotide sugar
  • The process is site specific

N-linked glycosylation

N-linked glycosylation of some proteins is required for proper folding. The N-linked glycosylation process occurs in eukaryotes and widely in archaea, but very rarely in prokaryotes.

For N-linked oligosaccharides, a 14-sugar precursor is first added to the asparagine in the polypeptide chain of the target protein. The structure of this precursor is common to most eukaryotes, and contains 3 glucose, 9 mannose, and 2 N-acetylglucosamine molecules. A complex set of reactions attaches this branched chain to a carrier molecule called dolichol, and then it is transferred to the appropriate point on the polypeptide chain as it is translocated into the ER lumen.

There are two major types of N-linked saccharides: high-mannose oligosaccharides, and complex oligosaccharides (Alberts et. al., Ch 13, pg 604). High-mannose is essentially just two N-acetylglucosamines with many mannose residues, often almost as many as are seen in the precursor oligosaccharides before it is attached to the protein. Complex oligosaccharides are so named because they can contain almost any number of the other types of saccharides, including more than the original two N-acetylglucosamines. Proteins can be glycosylated by both types of oligos on different portions of the protein. Whether an oligosaccharide is high-mannose or complex is thought to depend on its accessibility to saccharide-modifying proteins in the Golgi. If the saccharide is relatively inaccessible, it will most likely stay in its original high-mannose form. If it is accessible, then it is likely that many of the mannose residues will be cleaved off and the saccharide will be further modified by the addition of other types of group as discussed above.

The oligosaccharide chain is attached only to asparagine occurring in the tripeptide sequence Asn-X-Ser or Asn-X-Thr, where X could be any amino acid but not Pro, through the action of oligosaccharyl transferase. After attachment, once the protein is correctly folded, the three glucose residues are removed from the chain and the protein is available for export from the ER. The glycoprotein thus formed is then transported to the Golgi where removal of further mannose residues may take place. It should be noted, however, that glycosylation itself does not seem to be as necessary for correct transport targeting of the protein as one might think. Studies involving drugs that block certain steps in glycosylation, or mutant cells deficient in a glycosylation enzyme, still produce otherwise structurally normal proteins that are correctly targeted, and this interference does not seem to interfere severely with the viability of the cells. Mature glycoproteins may contain a variety of oligomannose N-linked oligosaccharides containing between 5 and 9 mannose residues. Further removal of mannose residues leads to a 'core' structure containing 3 mannose, and 2 N-acetylglucosamine residues which may then be elongated with a variety of different monosaccharides including galactose, N-acetylglucosamine, N-acetylgalactosamine, fucose and sialic acid.

O-linked glycosylation

O-linked glycosylation occurs at a later stage during protein processing, probably in the Golgi apparatus. This is the addition of N-acetyl-galactosamine to serine or threonine residues by the enzyme UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase, followed by other carbohydrates (such as galactose and sialic acid). This process is important for certain types of proteins such as proteoglycans, which involves the addition of glycosaminoglycan chains to an initially unglycosylated "proteoglycan core protein." These additions are usually serine O-linked glycoproteins which seem to have one of two main functions. One is secretion to form components of the extracellular matrix, adhereing one cell to another by interactions between the large sugar complexes of proteoglycans. The other main function is to act as a component of mucosal secretions, and it is the high concentration of carbohydrates which tends to give mucus its "slimy" feel. Proteins that circulate in the blood are not normally O-glycosylated, with the exception of IgA1 and IgD (two types of antibody) and C1-inhibitor.

GPI anchor

A special form of glycosylation is the GPI anchor. Although this is a form of glycosylation, the result is a hydrophobic side chain, making GPI anchoring quite similar to prenylation.

See also

References

  • Alberts, Bruce; Bray, Dennis; Lewis, Julian; Raff, Martin; Roberts, Keith; Watson, James. Molecular Biology of the Cell (3rd ed). Garland Publishing, 1983. ISBN 0-8153-1619-4.
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