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. 2017 Mar 4;11(2):82-88.
doi: 10.1080/19336896.2017.1301338. Epub 2017 Mar 21.

Limited understanding of the functional diversity of N-linked glycans as a major gap of prion biology

Ilia V Baskakov  1
Affiliations

Limited understanding of the functional diversity of N-linked glycans as a major gap of prion biology

Ilia V Baskakov. Prion. .

Abstract

Among a broad range of hypotheses on the molecular nature of transmissible spongiform encephalopathy or scrapie agents discussed in 1960s was a hypothesis of self-replicating polysaccharides. While the studies of the past 40 years provided unambiguous proof that this is not the case, emerging evidence suggests that carbohydrates in the form of sialylated N-linked glycans, which are a constitutive part of mammalian prions or PrPSc, are essential in determining prion fate in an organism. The current extra-view article discusses recent advancements on the role of N-linked glycans and specifically their sialylation status in controlling prion fate. In addition, this manuscript introduces a new concept on the important role of strain-specific functional carbohydrate epitopes on the PrPSc surface as main determinants of strain-specific biologic features. According to this concept, individual strain-specific folding patterns of PrPSc govern selection of PrPC sialoglycoforms expressed by a host that can be accommodated within particular PrPSc structures. Strain-specific patterns of functional carbohydrate epitopes formed by N-linked glycans on PrPSc surfaces define strain-specific biologic features. As a constitutive part of PrPSc, the individual strain-specific patterns of carbohydrate epitopes propagate faithfully within a given host as long as individual strain-specific PrPSc structures are maintained, ensuring inheritance of strain-specific biologic features.

Keywords: N-linked glycans; carbohydrate epitopes; microglia; prion; prion diseases; secondary lymphoid organs; sialic acid; sialylation.

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Figures

FIGURE 1.
FIGURE 1.
(A) Structures of bi-, tri-, and tetraantennary N-linked glycans found in PrPC and PrPSc that could be bisected (b) or nonbisected (n). Facultative fucosialtion and sialylation are shown within parenthesis with several sialic acid residues per glycan indicated. (B) Structures of pentatantennary and nonconventional N-liked glycans that can accommodate up to 5 sialic acid residues.
FIGURE 2.
FIGURE 2.
(A) Schematic diagram illustrating that PrPSc strains recruit PrPC isoforms selectively according to PrPC glycosylation and sialylation status (adopted from12). Strain #1 recruits sialoglycoforms of PrPC without noticeable preferences. Hypersialylated and diglycosylated PrPC are preferentially excluded from the strain #2 and even more so from the strain #3. As a result, the proportion of hyper- versus hyposialylated molecules within PrPSc (illustrated by the 2D Western blots), as well as the ratios of di-, mono- and unglycosylated glycoforms (shown on 1D Western blots on right hand side), changes in a strain-specific manner. PrPC molecules are shown as blue circles and sialic acid residues - as red diamonds. (B) Schematic diagram illustrates that species-specific amino acid sequences of PrPC determine the range of strain-specific folding patterns, which define the strain-specific patterns of functional carbohydrate epitopes on PrPSc surfaces within a particular host. Patterns of functional carbohydrate epitopes determine strain-specific biologic properties. PrPSc folding patterns are expected to be quite different for 2 groups of strains: (i) a group that can accommodate diglycosylated glycoforms and (ii) another group that selectively excludes diglycosylated glycoforms.
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Comment on

  • Extra View to: Srivastava S, Katorcha E, Daus ML, Lasch P, Beekes M, Baskakov IV. Sialylation controls prion fate in vivo. J Biol Chem 2017; 292(6): 2359-2368; http://dx.doi.org/10.1074/jbc.M116.768010

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