Dataset Information

Glycan-Induced Protein Dynamics in Human Norovirus P Dimers Depend on Virus Strain and Deamidation Status.

ABSTRACT: Noroviruses are the major cause of viral gastroenteritis and re-emerge worldwide every year, with GII.4 currently being the most frequent human genotype. The norovirus capsid protein VP1 is essential for host immune response. The P domain mediates cell attachment via histo blood-group antigens (HBGAs) in a strain-dependent manner but how these glycan-interactions actually relate to cell entry remains unclear. Here, hydrogen/deuterium exchange mass spectrometry (HDX-MS) is used to investigate glycan-induced protein dynamics in P dimers of different strains, which exhibit high structural similarity but different prevalence in humans. While the almost identical strains GII.4 Saga and GII.4 MI001 share glycan-induced dynamics, the dynamics differ in the emerging GII.17 Kawasaki 308 and rare GII.10 Vietnam 026 strain. The structural aspects of glycan binding to fully deamidated GII.4 P dimers have been investigated before. However, considering the high specificity and half-life of N373D under physiological conditions, large fractions of partially deamidated virions with potentially altered dynamics in their P domains are likely to occur. Therefore, we also examined glycan binding to partially deamidated GII.4 Saga and GII.4 MI001 P dimers. Such mixed species exhibit increased exposure to solvent in the P dimer upon glycan binding as opposed to pure wildtype. Furthermore, deamidated P dimers display increased flexibility and a monomeric subpopulation. Our results indicate that glycan binding induces strain-dependent structural dynamics, which are further altered by N373 deamidation, and hence hint at a complex role of deamidation in modulating glycan-mediated cell attachment in GII.4 strains.

SUBMITTER: Dulfer J

PROVIDER: S-EPMC8067865 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

Glycan-Induced Protein Dynamics in Human Norovirus P Dimers Depend on Virus Strain and Deamidation Status.

Dülfer Jasmin J Yan Hao H Brodmerkel Maxim N MN Creutznacher Robert R Mallagaray Alvaro A Peters Thomas T Caleman Carl C Marklund Erik G EG Uetrecht Charlotte C

Molecules (Basel, Switzerland) 20210407 8

Noroviruses are the major cause of viral gastroenteritis and re-emerge worldwide every year, with GII.4 currently being the most frequent human genotype. The norovirus capsid protein VP1 is essential for host immune response. The P domain mediates cell attachment via histo blood-group antigens (HBGAs) in a strain-dependent manner but how these glycan-interactions actually relate to cell entry remains unclear. Here, hydrogen/deuterium exchange mass spectrometry (HDX-MS) is used to investigate gly ...[more]

PMID: 33917179

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Project description:Noroviruses are non-enveloped (+) single stranded RNA viruses of the Caliciviridae family that cause an estimated 20 % of gastroenteritis cases worldwide . The virus possesses an icosahedral capsid, build by the two structural proteins VP1 and VP2. Noroviruses of genogroup II, especially GII.4, dominated in the majorities of outbreaks in the last two decades. In the last years, a novel GII.17 strain has also emerged in Asia. The major capsid protein VP1 builds dimers that are divided into the inner shell (S) domain and the outward-facing protruding (P) domain. The P domain is further divided into P1 and P2 subdomains, of which P2 is essential for host immune response and binds to histo blood-group antigens (HBGAs) for cell attachment in a strain-dependent manner, but the exact mechanism of cell attachment and entry remains unclear. Recently, a spontaneous deamidation of N373 with subsequent formation of an iso-aspartate (iD) was identified in GII.4 Saga P dimers that strongly attenuates glycan binding. This deamidation appears to be site specific and occurs in GII.4 MI001 P dimers as well, whereas it is absent in GII.10 Vietnam 026 and GII.17 Kawasaki 308 P dimers, which carry an Asp at the equivalent position. Given their high structural similarity with at the same time strain-dependent glycan binding behavior, we wanted to study if glycan binding induces different dynamic changes in P dimers of different strains using Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS). Furthermore, we wanted to examine the structural effects of fucose binding to a mixture of wildtype and deamidated GII.4 MI001 and GII.4 Saga P dimers, to get more insights about the dynamic changes induced by N373 deamidation. Our results suggest identical glycan binding behavior of the almost identical GII.4 Saga and GII.4 MI001 strains, but reveal different glycan induced dynamics in GII.17 Kawasaki 308 and GII.10 Vietnam 026. Furthermore, all strains apart from GII.4 Saga form a second P domain species that is highly protected from HDX . In mixtures of wildtype and N373 deamidated GII.4 P dimers, fucose binding leads to different structural dynamics than in pure wildtype, indicating that the deamidated species could have a biological function in vivo.

Dataset Information

Glycan-Induced Protein Dynamics in Human Norovirus P Dimers Depend on Virus Strain and Deamidation Status.

Publications

Glycan-Induced Protein Dynamics in Human Norovirus P Dimers Depend on Virus Strain and Deamidation Status.

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