Glycosylation

Glycosylation (see also chemical glycosylation) is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor). In biology glycosylation mainly refers in particular to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules. This enzymatic process produces one of the fundamental biopolymers found in cells (along with DNA, RNA, and proteins). Glycosylation is a form of co-translational and post-translational modification. Glycans serve a variety of structural and functional roles in membrane and secreted proteins.[1] The majority of proteins synthesized in the rough ER undergo glycosylation. It is an enzyme-directed site-specific process, as opposed to the non-enzymatic chemical reaction of glycation. Glycosylation is also present in the cytoplasm and nucleus as the O-GlcNAc modification. Aglycosylation is a feature of engineered antibodies to bypass glycosylation.[2][3] Five classes of glycans are produced:

Purpose

Glycosylation is the process by which a carbohydrate is covalently attached to a target macromolecule, typically proteins and lipids. This modification serves various functions.[4] For instance, some proteins do not fold correctly unless they are glycosylated.[1] In other cases, proteins are not stable unless they contain oligosaccharides linked at the amide nitrogen of certain asparagine. The influence of glycosylation on the folding and stability of glycoprotein is twofold. Firstly, the highly soluble glycans may have a direct physicochemical stabilisation effect. Secondly, N-linked glycan mediate a critical quality control check point in glycoprotein folding in the endoplasmic reticulum.[5] Glycosylation also plays a role in cell-cell adhesion (a mechanism employed by cells of the immune system) via sugar-binding proteins called lectins, which recognize specific carbohydrate moieties.[1] Glycosylation is an important parameter in the optimization of many glycoprotein-based drugs such as monoclonal antibodies.[5] Glycosylation also underpins the ABO blood group system. It is the presence or absence of glycosyltransferases which dictates which blood group antigens are presented and hence what antibody specificities are exhibited. This immunological role may well have driven the diversification of glycan heterogeneity and creates a barrier to zoonotic transmission of viruses.[6] In addition, glycosylation is often used by viruses to shield the underlying viral protein from immune recognition. A significant example is the dense glycan shield of the envelope spike of the human immunodeficiency virus.[7]

Overall, glycosylation needs to be understood by the likely evolutionary selection pressures that have shaped it. In one model, diversification can be considered purely as a result of endogenous functionality (such as cell trafficking). However, it is more likely that diversification is driven by evasion of pathogen infection mechanism (e.g. Helicobacter attachment to terminal saccharide residues) and that diversity within the multicellular organism is then exploited endogenously.

Glycoprotein Diversity

Glycosylation increases diversity in the proteome, because almost every aspect of glycosylation can be modified, including:

Mechanisms

There are various mechanisms for glycosylation, although most share several common features:[1]

Types of glycosylation

N-linked glycosylation

N-linked glycosylation is a very prevalent form of glycosylation and is important for the folding of many eukaryotic glycoproteins and for cell-cell and cell-extracellular matrix attachment. The N-linked glycosylation process occurs in eukaryotes in the lumen of the endoplasmic reticulum and widely in archaea, but very rarely in bacteria. In addition to their function in protein folding and cellular attachment, the N-linked glycans of a protein can modulate a protein's function, in some cases acting as an on-off switch.[9]

O-linked glycosylation

O-linked glycosylation is a form of glycosylation that occurs in eukaryotes in the Golgi apparatus,[10] but also occurs in archaea and bacteria.

Phospho-serine glycosylation

Xylose, fucose, mannose, and GlcNAc phosphoserine glycans have been reported in the literature. Fucose and GlcNAc have been found only in Dictyostelium discoideum, mannose in Leishmania mexicana, and xylose in Trypanosoma cruzi. Mannose has recently been reported in a vertebrate, the mouse, Mus musculus, on the cell-surface laminin receptor alpha dystroglycan4. It has been suggested this rare finding may be linked to the fact that alpha dystroglycan is highly conserved from lower vertebrates to mammals.[11]

C-mannosylation

A mannose sugar is added to the first tryptophan residue in the sequence W-X-X-W (W indicates tryptophan; X is any amino acid). Thrombospondins are one of the most commonly C-modified proteins, although this form of glycosylation appears elsewhere as well. C-mannosylation is unusual because the sugar is linked to a carbon rather than a reactive atom such as nitrogen or oxygen. Recently, the first crystal structure of a protein containing this type of glycosylation has been determined - that of human complement component 8, PDB ID 3OJY.

Formation of GPI anchors (glypiation)

A special form of glycosylation is the formation of a GPI anchor. In this kind of glycosylation a protein is attached to a lipid anchor, via a glycan chain. (See also prenylation.)

Clinical

Over 40 disorders of glycosylation have been reported in humans.[12] These can be divided into four groups: disorders of protein N-glycosylation, disorders of protein O-glycosylation, disorders of lipid glycosylation and disorders of other glycosylation pathways and of multiple glycosylation pathways. No effective treatment is known for any of these disorders. 80% of these affect the nervous system.

See also

References

  1. 1 2 3 4 Essentials of Glycobiology. Ajit Varki (ed.) (2nd ed.). Cold Spring Harbor Laboratories Press. ISBN 978-0-87969-770-9.
  2. ↑ Jung ST, Kang TH, Kelton W, Georgiou G (2011). "Bypassing glycosylation: engineering aglycosylated full-length IgG antibodies for human therapy". Curr Opin Biotechnol. 22: 858–67. doi:10.1016/j.copbio.2011.03.002. PMID 21420850.
  3. ↑ "Transgenic plants of Nicotiana tabacum L. express aglycosylated monoclonal antibody with antitumor activity". Biotecnologia Aplicada. 2013.
  4. ↑ Drickamer, K; M.E. Taylor (2006). Introduction to Glycobiology (2nd ed.). Oxford University Press, USA. ISBN 978-0-19-928278-4.
  5. 1 2 Dalziel, M; Crispin, M; Scanlan, CN; Zitzmann, N; Dwek, RA (Jan 2014). "Emerging principles for the therapeutic exploitation of glycosylation". Science. 343 (6166): 1235681. doi:10.1126/science.1235681.
  6. ↑ Crispin, Max; Harvey, David J.; Bitto, David; Bonomelli, Camille; Edgeworth, Matthew; Scrivens, James H.; Huiskonen, Juha T.; Bowden, Thomas A. (2014-02-10). "Structural Plasticity of the Semliki Forest Virus Glycome upon Interspecies Transmission". Journal of Proteome Research. 13 (3): 1702–1712. doi:10.1021/pr401162k. PMC 4428802Freely accessible. PMID 24467287.
  7. ↑ Crispin, Max; Doores, Katie J (2015-04-01). "Targeting host-derived glycans on enveloped viruses for antibody-based vaccine design". Current Opinion in Virology. Viral pathogenesis • Preventive and therapeutic vaccines. 11: 63–69. doi:10.1016/j.coviro.2015.02.002.
  8. ↑ Walsh, Christopher (2006). Posttranslational modification of proteins: Expanding nature's inventory. Roberts and Co. Publishers, Englewood, CO. ISBN 0974707732.
  9. ↑ Maverakis E, Kim K, Shimoda M, Gershwin M, Patel F, Wilken R, Raychaudhuri S, Ruhaak LR, Lebrilla CB (2015). "Glycans in the immune system and The Altered Glycan Theory of Autoimmunity". J Autoimmun. 57 (6): 1–13. doi:10.1016/j.jaut.2014.12.002. PMC 4340844Freely accessible. PMID 25578468.
  10. ↑ William G. Flynne (2008). Biotechnology and Bioengineering. Nova Publishers. pp. 45–. ISBN 978-1-60456-067-1. Retrieved 13 November 2010.
  11. ↑ Yoshida-Moriguchi, T.; et al. (2010). "O-Mannosyl Phosphorylation of Alpha-Dystroglycan Is Required for Laminin Binding". Science. 327 (5961): 88–92. doi:10.1126/science.1180512.
  12. ↑ Jaeken, J (2013). "Congenital disorders of glycosylation". Handb Clin Neurol. 113: 1737–43. doi:10.1016/B978-0-444-59565-2.00044-7.

External links

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