Jump to main content
Jump to site search

Issue 15, 2018
Previous Article Next Article

The impact of O-glycan chemistry on the stability of intrinsically disordered proteins

Author affiliations

Abstract

Protein glycosylation is a diverse post-translational modification that serves myriad biological functions. O-linked glycans in particular vary widely in extent and chemistry in eukaryotes, with secreted proteins from fungi and yeast commonly exhibiting O-mannosylation in intrinsically disordered regions of proteins, likely for proteolysis protection, among other functions. However, it is not well understood why mannose is often the preferred glycan, and more generally, if the neighboring protein sequence and glycan have coevolved to protect against proteolysis in glycosylated intrinsically disordered proteins (IDPs). Here, we synthesized variants of a model IDP, specifically a natively O-mannosylated linker from a fungal enzyme, with α-O-linked mannose, glucose, and galactose moieties, along with a non-glycosylated linker. Upon exposure to thermolysin, O-mannosylation, by far, provides the highest extent of proteolysis protection. To explain this observation, extensive molecular dynamics simulations were conducted, revealing that the axial configuration of the C2-hydroxyl group (2-OH) of α-mannose adjacent to the glycan–peptide bond strongly influences the conformational features of the linker. Specifically, α-mannose restricts the torsions of the IDP main chain more than other glycans whose equatorial 2-OH groups exhibit interactions that favor perpendicular glycan–protein backbone orientation. We suggest that IDP stiffening due to O-mannosylation impairs protease action, with contributions from protein–glycan interactions, protein flexibility, and protein stability. Our results further imply that resistance to proteolysis is an important driving force for evolutionary selection of α-mannose in eukaryotic IDPs, and more broadly, that glycan motifs for proteolysis protection likely coevolve with the protein sequence to which they attach.

Graphical abstract: The impact of O-glycan chemistry on the stability of intrinsically disordered proteins

Back to tab navigation

Supplementary files

Publication details

The article was received on 23 Nov 2017, accepted on 19 Mar 2018 and first published on 20 Mar 2018


Article type: Edge Article
DOI: 10.1039/C7SC05016J
Citation: Chem. Sci., 2018,9, 3710-3715
  • Open access: Creative Commons BY license
  •   Request permissions

    The impact of O-glycan chemistry on the stability of intrinsically disordered proteins

    E. T. Prates, X. Guan, Y. Li, X. Wang, P. K. Chaffey, M. S. Skaf, M. F. Crowley, Z. Tan and G. T. Beckham, Chem. Sci., 2018, 9, 3710
    DOI: 10.1039/C7SC05016J

    This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Material from this article can be used in other publications provided that the correct acknowledgement is given with the reproduced material.

    Reproduced material should be attributed as follows:

    • For reproduction of material from NJC:
      [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC.
    • For reproduction of material from PCCP:
      [Original citation] - Published by the PCCP Owner Societies.
    • For reproduction of material from PPS:
      [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC.
    • For reproduction of material from all other RSC journals:
      [Original citation] - Published by The Royal Society of Chemistry.

    Information about reproducing material from RSC articles with different licences is available on our Permission Requests page.

Search articles by author

Spotlight

Advertisements