Glycoproteins are molecules that comprise protein and carbohydrate chains that are involved in many physiological functions including immunity. Many viruses have glycoproteins that help them enter bodily cells, but can also serve to be important therapeutic or preventative targets.
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What are glycoproteins?
Glycoproteins are proteins containing glycans attached to amino acid side chains. Glycans are oligosaccharide chains; which are saccharide polymers, that can attach to either lipids (glycolipids) or amino acids (glycoproteins). Typically, these bonds are formed through a process called glycosylation.
Glycosylation occurs on a majority of proteins post-translationally with most RER synthesized proteins undergoing glycosylation. There are different forms of glycosylation that attach specific glycans to proteins and lipids.
For example, N-glycosylation (attachment of glycans to nitrogen on the amine side chain of asparagine) and O-glycosylation (attachment of glycans to oxygen on serine and/or threonine). Specific sugars (glycans) that can be attached to proteins or lipids in humans include β-D-Glucose (Glc) and β-D-Galactose (Gal).
Glycoproteins in health & disease
Glycoproteins are incredibly diverse and serve many functions in the body. Some provide structure e.g. collagens, others are involved in immunity e.g. immunoglobulins (such as IgG). Mucins are secreted into mucus of the respiratory and digestive tracts where the specific mucins can retain water thus allowing mucus to serve as an effective lubricant.
Specific glycoproteins (and glycolipids) present on the surface of red blood cells determine blood group type. A-oligosaccharide for A group, B-oligosaccharide for B group, both A & B oligosaccharides for AB group, and the absence of both A & B for O group (H-oligosaccharide precursor only).
The presence of Rh factor (an antigen) determines Rh+ groups, whereas the absence of the Rh antigen leads to Rh- groups after ABO determination.
Certain hormones are glycoproteins including follicle-stimulating hormone (FSH) – a gonadotropin hormone that has several functions in development, growth, puberty, and reproduction. Others include erythropoietin – a cytokine secreted by the kidneys that stimulate red blood cell production in bone marrow in high levels in response to hypoxia (low levels normally).
Many viruses have surface glycoproteins called spike domains; S (including SARS-CoV-2; the virus causing COVID-19, discussed below) which enable viruses to bind to their target receptors and enter cells.
Normally these surface glycoproteins can also serve as natural neutralizing targets for antibodies produced by the body in fighting off an infection and conferring some degree of future immunity.
Some viruses including HIV, however, have heavily glycosylated S-domains with an abundance of glycans that interfere with antibody binding and recognition thus making viruses such as HIV more evasive and difficult to fully treat.
Glycoproteins and COVID-19
β-coronaviruses – including MERS-CoV (MERS), SARS-CoV (SARS), and SARS-CoV-2 (COVID19) – enter the respiratory (and digestive) epithelia through their spike glycoprotein (S). The viruses bind to the ACE2 receptor through their SB (spike domain B) – which appears ‘crown-like’ and gives rise to the name ‘corona’-virus.
Coronaviruses also require TMPRSS2 to prime the SB-glycoprotein to enter cells through endocytosis.
The SB domain of β-coronaviruses is also the main site for antibodies to neutralize the viruses. It is also therefore the goal of successful vaccination to target the S glycoprotein on the surface of SARS-CoV-2. Furthermore, polyclonal sera has been shown in mice to inhibit SARS-CoV-2 entry into cells by blocking the SB domain.
SARS dissipated from the population and MERS was limited to the Middle East, thus the need for vaccines was not a top priority. However, with COVID-19 being a global pandemic, the need to produce a successful vaccine quickly became a top global priority. Many vaccines have now been produced and are being distributed across the globe.
As with many coronaviruses and influenza viruses, the surface S-domains are constantly changing (mutating) hence why there are seasonal epidemics each year, despite the presence of antibodies for previous strains.
SARS-CoV-2 has now mutated into many different variants, with some changes to the viral structure of the S-domain in recent variants. This has caused concern over the possibility of altering transmission or the effectiveness of vaccines.
In summary, glycoproteins are molecules of oligosaccharides (glycans) linked to amino acid side chains of proteins that serve a multitude of physiological functions. These functions vary from structural support such as collagens to determining blood group type Glycoproteins are also present on virus surfaces that enable binding to bodily receptors.
SARS-CoV-2 (causes COVID-19) has a spike-domain (a glycoprotein) that binds to ACE2 receptors in the lungs and interfering with the spike domain has been a vaccine target as well as other therapeutic targets.
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