thumb|right|N-linked protein glycosylation (N-glycosylation of N-glycans) at [[Asparagine|Asn residues (Asn-x-Ser/Thr motifs) in glycoproteins.]]
Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. Secreted extracellular proteins are often glycosylated.
In proteins that have segments extending extracellularly, the extracellular segments are also often glycosylated. Glycoproteins are also often important integral membrane proteins, where they play a role in cell–cell interactions. It is important to distinguish endoplasmic reticulum-based glycosylation of the secretory system from reversible cytosolic-nuclear glycosylation. Glycoproteins of the cytosol and nucleus can be modified through the reversible addition of a single GlcNAc residue that is considered reciprocal to phosphorylation and the functions of these are likely to be an additional regulatory mechanism that controls phosphorylation-based signalling. In contrast, classical secretory glycosylation can be structurally essential. For example, inhibition of asparagine-linked, i.e. N-linked, glycosylation can prevent proper glycoprotein folding and full inhibition can be toxic to an individual cell. In contrast, perturbation of glycan processing (enzymatic removal/addition of carbohydrate residues to the glycan), which occurs in both the endoplasmic reticulum and Golgi apparatus, is dispensable for isolated cells (as evidenced by survival with glycosides inhibitors) but can lead to human disease (congenital disorders of glycosylation) and can be lethal in animal models. It is therefore likely that the fine processing of glycans is important for endogenous functionality, such as cell trafficking, but that this is likely to have been secondary to its role in host-pathogen interactions. A famous example of this latter effect is the ABO blood group system.
Though there are different types of glycoproteins, the most common are N-linked and O-linked glycoproteins. These two types of glycoproteins are distinguished by structural differences that give them their names. Glycoproteins vary greatly in composition, making many different compounds such as antibodies or hormones. Due to the wide array of functions within the body, interest in glycoprotein synthesis for medical use has increased. There are now several methods to synthesize glycoproteins, including recombination and glycosylation of proteins.
Types of glycosylation
There are several types of glycosylation, although the first two are the most common.
- In N-glycosylation, sugars are attached to nitrogen, typically on the amide side-chain of asparagine.
- In O-glycosylation, sugars are attached to oxygen, typically on serine or threonine, but also on tyrosine or non-canonical amino acids such as hydroxylysine and hydroxyproline.
- In P-glycosylation, sugars are attached to phosphorus on a phosphoserine.
- In C-glycosylation, sugars are attached directly to carbon, such as in the addition of mannose to tryptophan.
- In S-glycosylation, a beta-GlcNAc is attached to the sulfur atom of a cysteine residue.
- In glypiation, a GPI glycolipid is attached to the C-terminus of a polypeptide, serving as a membrane anchor.
- In glycation, also known as non-enzymatic glycosylation, sugars are covalently bonded to a protein or lipid molecule, without the controlling action of an enzyme, but through a Maillard reaction.
Monosaccharides
thumb|Eight sugars commonly found in glycoproteins.
Monosaccharides commonly found in eukaryotic glycoproteins include:
{| class="wikitable"
|+The principal sugars found in human glycoproteins
|-
! Sugar
! Type
! Abbreviation
|-
| β-D-Glucose
| Hexose
| Glc
|-
| β-D-Galactose
| Hexose
| Gal
|-
| β-D-Mannose
| Hexose
| Man
|-
| α-L-Fucose
| Deoxyhexose
| Fuc
|-
| N-Acetylgalactosamine
| Aminohexose
| GalNAc
|-
| N-Acetylglucosamine
| Aminohexose
| GlcNAc
|-
| N-Acetylneuraminic acid
| Aminononulosonic acid<br />(Sialic acid)
| NeuNAc
|-
| Xylose
| Pentose
| Xyl
|-
|}
The sugar group(s) can assist in protein folding, improve proteins' stability and are involved in cell signalling.
Structure
thumb|487x487px|N-linked and O-linked glycoproteins
The critical structural element of all glycoproteins is having oligosaccharides bonded covalently to a protein.
Examples
The unique interaction between the oligosaccharide chains have different applications. First, it aids in quality control by identifying misfolded proteins.
Variable surface glycoproteins allow the sleeping sickness Trypanosoma parasite to escape the immune response of the host.
The viral spike of the human immunodeficiency virus is heavily glycosylated. Approximately half the mass of the spike is glycosylation and the glycans act to limit antibody recognition as the glycans are assembled by the host cell and so are largely 'self'. Over time, some patients can evolve antibodies to recognise the HIV glycans and almost all so-called 'broadly neutralising antibodies (bnAbs) recognise some glycans. This is possible mainly because the unusually high density of glycans hinders normal glycan maturation and they are therefore trapped in the premature, high-mannose, state. This provides a window for immune recognition. In addition, as these glycans are much less variable than the underlying protein, they have emerged as promising targets for vaccine design.
P-glycoproteins are critical for antitumor research due to its ability block the effects of antitumor drugs. P-glycoprotein, or multidrug transporter (MDR1), is a type of ABC transporter that transports compounds out of cells. Due to the unique abilities of glycoproteins, they can be used in many therapies.
</references>