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

Chemical Science
Erica T PratesGregg T Beckham

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 restrict...Continue Reading

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Citations

Mar 30, 2019·Journal of Peptide Science : an Official Publication of the European Peptide Society·Claudia BelloAnna Maria Papini
Apr 10, 2020·Scientific Reports·Shyamili GouthamRamray Bhat
Nov 1, 2020·International Journal of Biological Macromolecules·Yoshito AbeTadashi Ueda
Feb 7, 2021·Advanced Drug Delivery Reviews·Raoul Walther, Alexander N Zelikin
Aug 28, 2021·Journal of Proteomics·Simon Ngao MuleGiuseppe Palmisano

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Methods Mentioned

BETA
protein folding
glycosylation

Software Mentioned

REMD

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