Glycoprotein

Glycoproteins are proteins which contain oligosaccharide chains

(glycans) 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 N-linked protein glycosylation (N-
nucleus can be modified through the reversible addition of a single glycosylation of N-glycans) at Asn
GlcNAc residue that is considered reciprocal to phosphorylation and residues (Asn-x-Ser/Thr motifs) in
the functions of these are likely to be additional regulatory mechanism glycoproteins.[1]
that controls phosphorylation-based signalling.[2] 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 evidence 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.

Glycosylation is also known to occur on nucleocytoplasmic proteins in the form of O-GlcNAc.[3]

Contents
Types of glycosylation
Monosaccharides
Examples
Hormones
Functions
Analysis
See also
Notes and references
External links

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 & 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.[4]
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
Monosaccharides commonly found in eukaryotic glycoproteins
include:[5]:526

The principal sugars found in human glycoproteins[6]

Sugar Type Abbreviation
β-D-Glucose Hexose Glc
β-D-Galactose Hexose Gal
β-D-Mannose Hexose Man
α-L-Fucose Deoxyhexose Fuc Eight sugars commonly found in
glycoproteins.
N-Acetylgalactosamine Aminohexose GalNAc
N-Acetylglucosamine Aminohexose GlcNAc
Aminononulosonic acid
N-Acetylneuraminic acid NeuNAc
(Sialic acid)
Xylose Pentose Xyl

The sugar group(s) can assist in protein folding, improve proteins' stability and are involved in cell signalling.

Examples
One example of glycoproteins found in the body is mucins, which are secreted in the mucus of the respiratory
and digestive tracts. The sugars when attached to mucins give them considerable water-holding capacity and
also make them resistant to proteolysis by digestive enzymes.

Glycoproteins are important for white blood cell recognition. Examples of glycoproteins in the immune system
are:

molecules such as antibodies (immunoglobulins), which interact directly with antigens.

molecules of the major histocompatibility complex (or MHC), which are expressed on the
surface of cells and interact with T cells as part of the adaptive immune response.
 sialyl Lewis X antigen on the surface of leukocytes.

H antigen of the ABO blood compatibility antigens. Other examples of glycoproteins include:

gonadotropins (luteinizing hormone a follicle-stimulating hormone)

glycoprotein IIb/IIIa, an integrin found on platelets that is required for normal platelet
aggregation and adherence to the endothelium.
components of the zona pellucida, which surrounds the oocyte, and is important for sperm-egg
interaction.
structural glycoproteins, which occur in connective tissue. These help bind together the fibers,
cells, and ground substance of connective tissue. They may also help components of the tissue
bind to inorganic substances, such as calcium in bone.
Glycoprotein-41 (gp41) and glycoprotein-120 (gp120) are HIV viral coat proteins.

Soluble glycoproteins often show a high viscosity, for example, in egg white and blood plasma.

Miraculin, is a glycoprotein extracted from Synsepalum dulcificum a berry which alters human
tongue receptors to recognize sour foods as sweet.[7]

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.[8] 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.[9][10] 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.[11]

Hormones
Hormones that are glycoproteins include:

Follicle-stimulating hormone
Luteinizing hormone
Thyroid-stimulating hormone
Human chorionic gonadotropin
Alpha-fetoprotein
Erythropoietin (EPO)

Functions
 Some functions served by glycoproteins[5]:524
Function Glycoproteins
Structural molecule Collagens
Lubricant and protective
Mucins
agent
Transport molecule Transferrin, ceruloplasmin

Immunologic molecule Immunoglobulins,[12] histocompatibility antigens

Hormone Human chorionic gonadotropin (HCG), thyroid-stimulating hormone (TSH)
Enzyme Various, e.g., alkaline phosphatase, patatin
Cell attachment- Various proteins involved in cell–cell (e.g., sperm–oocyte), virus–cell, bacterium–cell,
recognition site and hormone–cell interactions
Antifreeze protein Certain plasma proteins of coldwater fish
Interact with specific
Lectins, selectins (cell adhesion lectins), antibodies
carbohydrates
Receptor Various proteins involved in hormone and drug action
Affect folding of certain
Calnexin, calreticulin
proteins
Regulation of
Notch and its analogs, key proteins in development
development
Hemostasis (and
Specific glycoproteins on the surface membranes of platelets
thrombosis)

Analysis
A variety of methods used in detection, purification, and structural analysis of glycoproteins are[5]:525[12][13]
 Some important methods used to study glycoproteins
Method Use
Periodic acid-
Detects glycoproteins as pink bands after electrophoretic separation.
Schiff stain
Incubation of
cultured cells
with
Leads to detection of a radioactive sugar after electrophoretic separation.
glycoproteins as
radioactive
decay bands
Treatment with
appropriate
endo- or Resultant shifts in electrophoretic migration help distinguish among proteins with N-glycan, O-
exoglycosidase glycan, or GPI linkages and also between high mannose and complex N-glycans.
or
phospholipases
Agarose-lectin
column
chromatography, To purify glycoproteins or glycopeptides that bind the particular lectin used.
lectin affinity
chromatography
Lectin affinity Resultant shifts in electrophoretic migration help distinguish and characterize glycoforms, i.e.
electrophoresis variants of a glycoprotein differing in carbohydrate.
Compositional
analysis
Identifies sugars that the glycoprotein contains and their stoichiometry.
following acid
hydrolysis

Mass Provides information on molecular mass, composition, sequence, and sometimes branching of a
spectrometry glycan chain. It can also be used for site-specific glycosylation profiling.[12]
NMR
To identify specific sugars, their sequence, linkages, and the anomeric nature of glycosidic chain.
spectroscopy
In conjunction with size-exclusion chromatography, UV/Vis absorption and differential
refractometry, provides information on molecular mass, protein-carbohydrate ratio, aggregation
Multi-angle light
state, size, and sometimes branching of a glycan chain. In conjunction with composition-gradient
scattering
analysis, analyzes self- and hetero-association to determine binding affinity and stoichiometry
with proteins or carbohydrates in solution without labeling.
Dual
Measures the mechanisms underlying the biomolecular interactions, including reaction rates,
Polarisation
affinities and associated conformational changes.
Interferometry
Methylation
(linkage) To determine linkage between sugars.
analysis
Amino acid or
cDNA Determination of amino acid sequence.
sequencing

See also
Ero1
Female sperm storage
Glycocalyx
Glycome
Glycopeptide
 Gp120
Gp41
Miraculin
P-glycoprotein
Proteoglycan
Ribophorin

Notes and references

1. Ruddock, L. W.; Molinari, M. (2006). "N-glycan processing in ER quality control" (https://doi.org/
10.1242/jcs.03225). Journal of Cell Science. 119 (21): 4373–4380. doi:10.1242/jcs.03225 (http
s://doi.org/10.1242%2Fjcs.03225). PMID 17074831 (https://pubmed.ncbi.nlm.nih.gov/1707483
1).
2. Funakoshi Y, Suzuki T (January 2009). "Glycobiology in the cytosol: The bitter side of a sweet
world". Biochim. Biophys. Acta. 1790 (2): 81–94. doi:10.1016/j.bbagen.2008.09.009 (https://doi.
org/10.1016%2Fj.bbagen.2008.09.009). PMID 18952151 (https://pubmed.ncbi.nlm.nih.gov/189
52151).
3. Gw, Hart (27 October 2014). "Three Decades of Research on O-GlcNAcylation - A Major
Nutrient Sensor That Regulates Signaling, Transcription and Cellular Metabolism" (https://pub
med.ncbi.nlm.nih.gov/25386167/). Frontiers in endocrinology. PMID 25386167 (https://pubmed.
ncbi.nlm.nih.gov/25386167). Retrieved 1 June 2020.
4. Stepper, Judith; Shastri, Shilpa; Loo, Trevor S.; Preston, Joanne C.; Novak, Petr; Man, Petr;
Moore, Christopher H.; Havlíček, Vladimír; Patchett, Mark L. (18 January 2011). "CysteineS-
glycosylation, a new post-translational modification found in glycopeptide bacteriocins". FEBS
Letters. 585 (4): 645–650. doi:10.1016/j.febslet.2011.01.023 (https://doi.org/10.1016%2Fj.febsle
t.2011.01.023). ISSN 0014-5793 (https://www.worldcat.org/issn/0014-5793). PMID 21251913 (h
ttps://pubmed.ncbi.nlm.nih.gov/21251913).
5. Robert K. Murray, Daryl K. Granner & Victor W. Rodwell: "Harper's Illustrated Biochemistry 27th
Ed.", McGraw–Hill, 2006
6. Glycan classification (https://www.sigmaaldrich.com/img/assets/15880/glycan_classification.pd
f) SIGMA
7. Theerasilp S, Kurihara Y (August 1988). "Complete purification and characterization of the
taste-modifying protein, miraculin, from miracle fruit" (http://www.jbc.org/cgi/reprint/263/23/1153
6). J. Biol. Chem. 263 (23): 11536–9. PMID 3403544 (https://pubmed.ncbi.nlm.nih.gov/340354
4).
8. Pritchard, Laura K.; Vasiljevic, Snezana; Ozorowski, Gabriel; Seabright, Gemma E.; Cupo,
Albert; Ringe, Rajesh; Kim, Helen J.; Sanders, Rogier W.; Doores, Katie J. (16 June 2015).
"Structural Constraints Determine the Glycosylation of HIV-1 Envelope Trimers" (https://www.nc
bi.nlm.nih.gov/pmc/articles/PMC4555872). Cell Reports. 11 (10): 1604–1613.
doi:10.1016/j.celrep.2015.05.017 (https://doi.org/10.1016%2Fj.celrep.2015.05.017).
ISSN 2211-1247 (https://www.worldcat.org/issn/2211-1247). PMC 4555872 (https://www.ncbi.nl
m.nih.gov/pmc/articles/PMC4555872). PMID 26051934 (https://pubmed.ncbi.nlm.nih.gov/2605
1934).
9. Pritchard, Laura K.; Spencer, Daniel I. R.; Royle, Louise; Bonomelli, Camille; Seabright,
Gemma E.; Behrens, Anna-Janina; Kulp, Daniel W.; Menis, Sergey; Krumm, Stefanie A. (24
June 2015). "Glycan clustering stabilizes the mannose patch of HIV-1 and preserves
vulnerability to broadly neutralizing antibodies" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC
4500839). Nature Communications. 6: 7479. Bibcode:2015NatCo...6.7479P (https://ui.adsabs.h
arvard.edu/abs/2015NatCo...6.7479P). doi:10.1038/ncomms8479 (https://doi.org/10.1038%2Fn
comms8479). PMC 4500839 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500839).
PMID 26105115 (https://pubmed.ncbi.nlm.nih.gov/26105115).
10. Behrens, Anna-Janina; Vasiljevic, Snezana; Pritchard, Laura K.; Harvey, David J.; Andev,
Rajinder S.; Krumm, Stefanie A.; Struwe, Weston B.; Cupo, Albert; Kumar, Abhinav (10 March
2016). "Composition and Antigenic Effects of Individual Glycan Sites of a Trimeric HIV-1
Envelope Glycoprotein" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805854). Cell
Reports. 14 (11): 2695–2706. doi:10.1016/j.celrep.2016.02.058 (https://doi.org/10.1016%2Fj.ce
lrep.2016.02.058). ISSN 2211-1247 (https://www.worldcat.org/issn/2211-1247). PMC 4805854
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805854). PMID 26972002 (https://pubmed.ncb
i.nlm.nih.gov/26972002).
11. Crispin, Max; Doores, Katie J (1 April 2015). "Targeting host-derived glycans on enveloped
viruses for antibody-based vaccine design" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC482
7424). Current Opinion in Virology. Viral pathogenesis • Preventive and therapeutic vaccines.
11: 63–69. doi:10.1016/j.coviro.2015.02.002 (https://doi.org/10.1016%2Fj.coviro.2015.02.002).
PMC 4827424 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827424). PMID 25747313 (http
s://pubmed.ncbi.nlm.nih.gov/25747313).
12. 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" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340844). J Autoimmun. 57 (6):
1–13. doi:10.1016/j.jaut.2014.12.002 (https://doi.org/10.1016%2Fj.jaut.2014.12.002).
PMC 4340844 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340844). PMID 25578468 (http
s://pubmed.ncbi.nlm.nih.gov/25578468).
13. Dell A (2001). "Glycoprotein Structure Determination by Mass Spectrometry". Science. 291
(5512): 2351–2356. Bibcode:2001Sci...291.2351D (https://ui.adsabs.harvard.edu/abs/2001Sc
i...291.2351D). doi:10.1126/science.1058890 (https://doi.org/10.1126%2Fscience.1058890).
ISSN 0036-8075 (https://www.worldcat.org/issn/0036-8075). PMID 11269315 (https://pubmed.n
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External links
Glycan Recognizing Proteins (http://www.bio-world.com/glycobiology/lectins.html)
Structure of Glycoprotein and Carbohydrate Chain (http://www.ecosci.jp/chem10/weekmol101j
_e.html) – Home Page for Learning Environmental Chemistry
Biochemistry 5thE 11.3. Carbohydrates Can Be Attached to Proteins to Form Glycoproteins (htt
ps://www.ncbi.nlm.nih.gov/books/bv.fcgi?indexed=google&rid=stryer.section.1531)
Carbohydrate Chemistry and Glycobiology: A Web Tour (http://www.sciencemag.org/feature/dat
a/carbohydrates.dtl#glycoproteins) SPECIAL WeB SUPPLEMENT Science 23 March 2001 Vol
291, Issue 5512, Pages 2263–2502
Glycoproteins (https://meshb.nlm.nih.gov/record/ui?name=Glycoproteins) at the US National
Library of Medicine Medical Subject Headings (MeSH)
Emanual Maverakis; et al. "Glycans in the immune system and The Altered Glycan Theory of
Autoimmunity" (http://ac.els-cdn.com/S0896841114001759/1-s2.0-S0896841114001759-main.
pdf?_tid=fbc3820c-0881-11e5-b633-00000aacb362&acdnat=1433179187_223619b43246b42
b6d0f8c696bf10ac7) (PDF).
Biological Importance of the glycosylation of a protein (http://www.biochempages.com/2015/08/
biological-importance-of-the-glycosylation-of-the-proteins.html)

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