Fogarty, Carl A and Fadda, Elisa (2021) Oligomannose N-Glycans 3D Architecture and Its Response to the FcγRIIIa Structural Landscape. The Journal of Physical Chemistry B, 125 (10). pp. 2607-2616. ISSN 1520-6106

Preview

Download (6MB) | Preview

Abstract

Oligomannoses are evolutionarily the oldest class of N-glycans, where the arms of the common pentasaccharide unit, i.e., Manα(1−6)-[Manα(1−3)]-Manβ(1−4)-GlcNAcβ(1−4)- GlcNAcβ1-Asn, are functionalized exclusively with branched arrangements of mannose (Man) monosaccharide units. In mammalian species oligomannose N-glycans can have up to 9 Man; meanwhile structures can grow to over 200 units in yeast mannan. The highly dynamic nature, branching complexity, and 3D structure of oligomannoses have been recently highlighted for their roles in immune escape and infectivity of enveloped viruses, such as HIV-1 and SARS-CoV2. The architectural features that allow these N-glycans to perform their functions are yet unclear, due to their intrinsically disordered nature that hinders their structural characterization. In this work we will discuss the results of over 54 μs of cumulative sampling by molecular dynamics (MD) simulations of differently processed, free (not protein-linked) oligomannose N-glycans common in vertebrates. We then discuss the effects of a protein surface on their structural equilibria based on over 4 μs cumulative MD sampling of the fully glycosylated CD16a Fc γ receptor (FcγRIIIa), where the type of glycosylation is known to modulate its binding affinity for IgG1s, regulating the antibody-dependent cellular cytotoxicity (ADCC). Our results show that the protein’s structural constraints shift the oligomannoses conformational ensemble to promote conformers that satisfy the steric requirements and hydrogen bonding networks demanded by the protein’s surface landscape. More importantly, we find that the protein does not actively distort the N-glycans into structures not populated in the unlinked forms in solution. Ultimately, the highly populated conformations of the Man5 linked glycans support experimental evidence of high levels of hybrid complex forms at N45 and show a specific presentation of the arms at N162, which may be involved in mediating binding affinity to the IgG1 Fc.

Item Type:	Article
Additional Information:	Cite as: Fogarty, C.A. & Fadda, E. 2021, "Oligomannose N‑Glycans 3D Architecture and Its Response to the FcγRIIIa Structural Landscape", The journal of physical chemistry. B, vol. 125, no. 10, pp. 2607-2616
Keywords:	Carbohydrates;Chemical structure;Cluster chemistry;Conformation;Molecular structure
Academic Unit:	Faculty of Science and Engineering > Chemistry Faculty of Science and Engineering > Research Institutes > Hamilton Institute Faculty of Science and Engineering > Research Institutes > Human Health Institute
Item ID:	17387
Identification Number:	https://doi.org/10.1021/acs.jpcb.1c00304
Depositing User:	Elisa Fadda
Date Deposited:	06 Jul 2023 14:25
Journal or Publication Title:	The Journal of Physical Chemistry B
Publisher:	American Chemical Society
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

Repository Staff Only(login required)

Item control page

Downloads

Origin of downloads