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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
Prates, Erica T. [1, 2] ; Guan, Xiaoyang [3, 4] ; Li, Yaohao [3, 4] ; Wang, Xinfeng [3, 4] ; Chaffey, Patrick K. [3, 4] ; Skaf, Munir S. [2] ; Crowley, Michael F. [5] ; Tan, Zhongping [3, 4] ; Beckham, Gregg T. [1]
Total Authors: 9
Affiliation:
[1] Natl Renewable Energy Lab, Natl Bioenergy Ctr, Golden, CO 80403 - USA
[2] Univ Estadual Campinas, Ctr Computat Engn & Sci, Inst Chem, BR-13084862 Campinas, SP - Brazil
[3] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80303 - USA
[4] Univ Colorado, BioFrontiers Inst, Boulder, CO 80303 - USA
[5] Natl Renewable Energy Lab, Biosci Ctr, Golden, CO 80403 - USA
Total Affiliations: 5
Document type: Journal article
Source: CHEMICAL SCIENCE; v. 9, n. 15, p. 3710-3715, APR 21 2018.
Web of Science Citations: 3
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 alpha-O-linked mannose, glucose, and galactose moieties, along with a nonglycosylated 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 alpha-mannose adjacent to the glycan-peptide bond strongly influences the conformational features of the linker. Specifically, alpha-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 alpha-mannose in eukaryotic IDPs, and more broadly, that glycan motifs for proteolysis protection likely coevolve with the protein sequence to which they attach. (AU)

FAPESP's process: 13/08293-7 - CCES - Center for Computational Engineering and Sciences
Grantee:Munir Salomao Skaf
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 16/04775-5 - Multiscale simulations of enzymes and enzymatic complexes to lignocellulosic biomass degradation
Grantee:Érica Teixeira Prates
Support type: Scholarships abroad - Research Internship - Post-doctor