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The Complexity of Glycan Structures, Functions, and Origins

Russell W. Carlson

Russell W. Carlson

Complex Carbohydrate Research Center, Department of Biochemistry & Molecular Biology, University of GeorgiaAthens, USA
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Carlson, Russell W.
  
31 dic 2024
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Categoria dell'articolo: Review
Pubblicato online: 31 dic 2024
Pagine: 57 - 78
DOI: https://doi.org/10.2478/biocosmos-2024-0005
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© 2024 Russell W. Carlson, published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Figure 1.

A structural comparison of an amino acid (alanine), a nucleotide (adenosine), and a hexose (d-glucopyranose and d-glucofuranose). The reactive functional groups are indicated in red.
A structural comparison of an amino acid (alanine), a nucleotide (adenosine), and a hexose (d-glucopyranose and d-glucofuranose). The reactive functional groups are indicated in red.

Figure 2.

The ten most common saccharides found in mammalian cells and their symbols. The ‘*’ indicates the anomeric hydroxyl which can be present in either the α- or β-configuration; the β-configurations are shown here.
The ten most common saccharides found in mammalian cells and their symbols. The ‘*’ indicates the anomeric hydroxyl which can be present in either the α- or β-configuration; the β-configurations are shown here.

Figure 3.

A symbolic representation of the different classes of N-linked glycan structures attached to proteins. The definitions of the symbols are shown in Figure 2. The core region is indicated by the red dashed box. Various saccharides are attached to a core region to form a variety of high mannose, complex, or hybrid glycans. High mannose glycans consist mannose residues attached to the core region. Complex glycans can have a variety of different monosaccharides attached to the core region, and, while two branches are shown here, hybrid glycans exist with up to six branches. The branches on these complex structures all begin with a GlcNAc residue, and each branch can be extended with repeats of a Galβ1-4GlcNAc (i.e. LacNAc, N-acetyllactosamine) disaccharide. GlcNAc, N-acetylglucosamine.
A symbolic representation of the different classes of N-linked glycan structures attached to proteins. The definitions of the symbols are shown in Figure 2. The core region is indicated by the red dashed box. Various saccharides are attached to a core region to form a variety of high mannose, complex, or hybrid glycans. High mannose glycans consist mannose residues attached to the core region. Complex glycans can have a variety of different monosaccharides attached to the core region, and, while two branches are shown here, hybrid glycans exist with up to six branches. The branches on these complex structures all begin with a GlcNAc residue, and each branch can be extended with repeats of a Galβ1-4GlcNAc (i.e. LacNAc, N-acetyllactosamine) disaccharide. GlcNAc, N-acetylglucosamine.

Figure 4.

A schematic diagram of IgG is shown with oligosaccharides attached to the Fc portion of the heavy chain. Fc contains two glycosylation sites, and each site can remain unglycosylated or glycosylated with any one of 32 different oligosaccharide. As described in the text, it is the combination of glycoforms, the glycotype, of Fc which determines its interaction with FcRs and the resulting strength of the immune response. FcRs, Fc receptors.
A schematic diagram of IgG is shown with oligosaccharides attached to the Fc portion of the heavy chain. Fc contains two glycosylation sites, and each site can remain unglycosylated or glycosylated with any one of 32 different oligosaccharide. As described in the text, it is the combination of glycoforms, the glycotype, of Fc which determines its interaction with FcRs and the resulting strength of the immune response. FcRs, Fc receptors.

Figure 5.

The synthesis of the glycoprotein glycan precursor, Glc3Man9GlcNAc2. GTs are known as Alg (asparagine-linked glycan) enzymes. The initial Man5GlcNAc2-Dol is made on the cytoplasmic face of the ER using UDP-GlcNAc and GDP-Man as the activated sugars. This is then flipped to the lumen side of the ER membrane. Dol-PP-Man and Dol-PP-Glc are made from UDP-Glc and GDP-Man on the cytoplasmic side of the ER membrane and then flipped to the lumen side of the ER membrane where they are used as substrates to add the remaining 4 Man residues and 3 Glc residues to the glycan giving the Glc3Man9GlcNAc2-Dol structure. Stanley et al. (15). give a more detailed description in their chapter and in their Figure 9.3. ER, endoplasmic reticulum; Glc, glucose; GlcNAc, N-acetylglucosamine; GTs, glycosyl transferases; Man, mannose.
The synthesis of the glycoprotein glycan precursor, Glc3Man9GlcNAc2. GTs are known as Alg (asparagine-linked glycan) enzymes. The initial Man5GlcNAc2-Dol is made on the cytoplasmic face of the ER using UDP-GlcNAc and GDP-Man as the activated sugars. This is then flipped to the lumen side of the ER membrane. Dol-PP-Man and Dol-PP-Glc are made from UDP-Glc and GDP-Man on the cytoplasmic side of the ER membrane and then flipped to the lumen side of the ER membrane where they are used as substrates to add the remaining 4 Man residues and 3 Glc residues to the glycan giving the Glc3Man9GlcNAc2-Dol structure. Stanley et al. (15). give a more detailed description in their chapter and in their Figure 9.3. ER, endoplasmic reticulum; Glc, glucose; GlcNAc, N-acetylglucosamine; GTs, glycosyl transferases; Man, mannose.

Figure 6.

Attachment of the precursor glycan to a -Asn-X-Ser (where X is not Pro) site of the growing polypeptide, completion of the N-glycan precursor structure, and correct folding of the glycoprotein. GI and GII are glucosyl hydrolases, OSTA is the oligosaccharide transferase, UGGT is a glucosyl transferase, MAN1B1 and EDEM1-3 are mannosyl hydrolases. Details are as described in the text. A more detailed description of this process is given by Suzuki et al. (27) and shown in their Figure 39.2. ER, endoplasmic reticulum; GI, glucosidases.
Attachment of the precursor glycan to a -Asn-X-Ser (where X is not Pro) site of the growing polypeptide, completion of the N-glycan precursor structure, and correct folding of the glycoprotein. GI and GII are glucosyl hydrolases, OSTA is the oligosaccharide transferase, UGGT is a glucosyl transferase, MAN1B1 and EDEM1-3 are mannosyl hydrolases. Details are as described in the text. A more detailed description of this process is given by Suzuki et al. (27) and shown in their Figure 39.2. ER, endoplasmic reticulum; GI, glucosidases.

Figure 7.

Processing to the mature glycan structure in the Golgi. In this figure the addition of two Gal and two SA residues is shown, but other structures can be formed by the expression of various GTs that can add other branching GlcNAc residues, Fuc residues, as well as additional combinations of Gal, LacNAc disaccharides, and SA residues. Stanley et al. (15) describe this in more detail in their chapter and in their Figure 9.4. Fuc, fucose; Gal, galactose; GlcNAc, N-acetylglucosamine; GTs, glycosyl transferases.
Processing to the mature glycan structure in the Golgi. In this figure the addition of two Gal and two SA residues is shown, but other structures can be formed by the expression of various GTs that can add other branching GlcNAc residues, Fuc residues, as well as additional combinations of Gal, LacNAc disaccharides, and SA residues. Stanley et al. (15) describe this in more detail in their chapter and in their Figure 9.4. Fuc, fucose; Gal, galactose; GlcNAc, N-acetylglucosamine; GTs, glycosyl transferases.

Figure 8.

Fine-tuning of the inflammatory response via glycosylation of the Fc portion of IgG. The combination of Fc glycoforms interact with FcRs on the surface of various types of immune system cells to produce an inflammatory response. The strength of the response is determined by the composite interaction of these glycoforms with their receptors and this is determined by the structures of the glycans that are attached to each Fc glycoform. In this Figure, G0 stands for the GlcNAc2Man3GlcNAc2-Fc structure shown in the boxed region that lacks any Gal (G) residues, G0F for that structure with the added Fuc residue (F) through the action of the GT, FUT8. B stands for the addition of a branching GlcNAc residue by GNTIII. G1 strands for a Gal1GlcNAc2Man3GlcNAc2-Protein in which one Gal (G) residue has been added by B4GALT1. The addition of B and F as well as an additional G to these structures in various combinations can also occur. Similarly, the addition of sialic acid, SA (S), to the various combinations of galactosylated structures is done by ST6GAL1. These four GTs, FUT8, GNTIII, B4GALT1, and ST6GAL1, account for the specific combinations of Fc glycoforms that can subtilty shift the immune response toward a pro- or anti-inflammatory response. FcRs, Fc receptors; Fuc, fucose; Gal, galactose; GlcNAc, N-acetylglucosamine; GNTIII, N-acetylglucosaminosyl transferase III; GTs, glycosyl transferases.
Fine-tuning of the inflammatory response via glycosylation of the Fc portion of IgG. The combination of Fc glycoforms interact with FcRs on the surface of various types of immune system cells to produce an inflammatory response. The strength of the response is determined by the composite interaction of these glycoforms with their receptors and this is determined by the structures of the glycans that are attached to each Fc glycoform. In this Figure, G0 stands for the GlcNAc2Man3GlcNAc2-Fc structure shown in the boxed region that lacks any Gal (G) residues, G0F for that structure with the added Fuc residue (F) through the action of the GT, FUT8. B stands for the addition of a branching GlcNAc residue by GNTIII. G1 strands for a Gal1GlcNAc2Man3GlcNAc2-Protein in which one Gal (G) residue has been added by B4GALT1. The addition of B and F as well as an additional G to these structures in various combinations can also occur. Similarly, the addition of sialic acid, SA (S), to the various combinations of galactosylated structures is done by ST6GAL1. These four GTs, FUT8, GNTIII, B4GALT1, and ST6GAL1, account for the specific combinations of Fc glycoforms that can subtilty shift the immune response toward a pro- or anti-inflammatory response. FcRs, Fc receptors; Fuc, fucose; Gal, galactose; GlcNAc, N-acetylglucosamine; GNTIII, N-acetylglucosaminosyl transferase III; GTs, glycosyl transferases.

Figure 9.

The Type 1 and Type 2 FcRs. Recognition of Fc by these receptors either activate or inhibit the immune response. The Type I receptor, FcRIIb inhibits the response and its expression is increased by interaction with the Type II receptor, DC-SIGN. The Fc-FcR interactions are modulated by the pattern of Fc glycoforms (see Figure 9) as well as the pattern of glycoforms for each FcR which are also glycosylated. These interactions determine the overall activation/inhibition ratio as well as the fine-tuning of the various activation pathways (see text for details). ADCC, antibody-dependent cell cytotoxicity; FcRs, Fc receptors.
The Type 1 and Type 2 FcRs. Recognition of Fc by these receptors either activate or inhibit the immune response. The Type I receptor, FcRIIb inhibits the response and its expression is increased by interaction with the Type II receptor, DC-SIGN. The Fc-FcR interactions are modulated by the pattern of Fc glycoforms (see Figure 9) as well as the pattern of glycoforms for each FcR which are also glycosylated. These interactions determine the overall activation/inhibition ratio as well as the fine-tuning of the various activation pathways (see text for details). ADCC, antibody-dependent cell cytotoxicity; FcRs, Fc receptors.

Figure 10.

A schematic illustrating the transcriptional and translational regulatory networks that determine glycan structures. The actual complexity and intricacy of these networks is described in more detail by Groth et al. (67) and Thu and Mahal (68). The top portion of this figure illustrates translational regulation via TFs interacting with CRMs of various glycogenes and, thereby, activating their expression and resulting production of corresponding mRNAs (shown in the middle). Each TF can activate multiple genes and, therefore, different TFs may activate overlapping sets of glycogenes creating various GRNs. Translational regulation occurs by the action of miRNAs (shown in the bottom portion of this figure). As with TFs, a single miRNA can affect multiple mRNAs and different miRNAs can affect overlapping sets of glycogene mRNAs. It is also likely that the miRNA and TF networks interact to produce the correct glycan structures at the right time and place. Expression of glycogenes can also be affected by epigenetic factors. CRMs, cis-regulatory modules; GRNs, gene regulatory networks; miRNA, micro RNA; TFs, transcription factors.
A schematic illustrating the transcriptional and translational regulatory networks that determine glycan structures. The actual complexity and intricacy of these networks is described in more detail by Groth et al. (67) and Thu and Mahal (68). The top portion of this figure illustrates translational regulation via TFs interacting with CRMs of various glycogenes and, thereby, activating their expression and resulting production of corresponding mRNAs (shown in the middle). Each TF can activate multiple genes and, therefore, different TFs may activate overlapping sets of glycogenes creating various GRNs. Translational regulation occurs by the action of miRNAs (shown in the bottom portion of this figure). As with TFs, a single miRNA can affect multiple mRNAs and different miRNAs can affect overlapping sets of glycogene mRNAs. It is also likely that the miRNA and TF networks interact to produce the correct glycan structures at the right time and place. Expression of glycogenes can also be affected by epigenetic factors. CRMs, cis-regulatory modules; GRNs, gene regulatory networks; miRNA, micro RNA; TFs, transcription factors.

Figure 11.

Production of a tissue-specific protein glycotype, and a global cellular tissue-specific glycopattern. During the synthesis of multiple copies of a single protein, each copy can have a unique glycosylation pattern called a glycoform resulting a multiple glycoforms of that protein which is called a glycotype. The protein’s glycotype is tissue-specific. This specificity is determined by regulation of the various GTs and GHs via transcriptional and translational regulatory networks as depicted in Figure 10 and described in the text. The major structural diversity of glycans is produced during their maturation in the Golgi apparatus. The combination of various protein glycotypes as well as glycolipid glycotypes, and GAGs produce a globular cellular tissue-specific glycopattern. GAGs, glycosaminoglycans; GHs, glycosyl hydrolases; GTs, glycosyl transferases; miRNA, micro RNA; TFs, transcription factors.
Production of a tissue-specific protein glycotype, and a global cellular tissue-specific glycopattern. During the synthesis of multiple copies of a single protein, each copy can have a unique glycosylation pattern called a glycoform resulting a multiple glycoforms of that protein which is called a glycotype. The protein’s glycotype is tissue-specific. This specificity is determined by regulation of the various GTs and GHs via transcriptional and translational regulatory networks as depicted in Figure 10 and described in the text. The major structural diversity of glycans is produced during their maturation in the Golgi apparatus. The combination of various protein glycotypes as well as glycolipid glycotypes, and GAGs produce a globular cellular tissue-specific glycopattern. GAGs, glycosaminoglycans; GHs, glycosyl hydrolases; GTs, glycosyl transferases; miRNA, micro RNA; TFs, transcription factors.
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