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.
| Original language | English |
|---|---|
| Article number | 2125 |
| Journal | Molecules |
| Volume | 26 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 02.04.2021 |
Funding
Funding: J.D. and C.U. acknowledge funding from FOR2327 ViroCarb. C.U. acknowledges funding from the Leibniz Association through SAW-2014-HPI-4 grant. The Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology is supported by the Free and Hanseatic City of Hamburg and the Federal Ministry of Health. Computational resources were supplied through the Swedish National Infrastructure for Computing (SNIC) through the Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) and the High Performance Computing Center North (HPC2N) under project SNIC 2019/4-554 and 2020/5-100. C.C. acknowledges the Helmholtz Association through the CFEL at DESY and the Swedish Research Council. This work was supported by MS SPIDOC within the European Union’s Horizon 2020 research and innovation program under grant agreement No. 801406. J.D. and C.U. acknowledge funding from FOR2327 ViroCarb. C.U. acknowledges funding from the Leibniz Association through SAW-2014-HPI-4 grant. The Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology is supported by the Free and Hanseatic City of Hamburg and the Federal Ministry of Health. Computational resources were supplied through the Swedish National Infrastructure for Computing (SNIC) through the Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) and the High Performance Computing Center North (HPC2N) under project SNIC 2019/4-554 and 2020/5-100. C.C. acknowledges the Helmholtz Association through the CFEL at DESY and the Swedish Research Council. This work was supported by MS SPIDOC within the European Union?s Horizon 2020 research and innovation program under grant agreement No. 801406. J.D. and C.U. would like to thank Prof. H. Schl?ter (UKE, University of Ham-burg, Germany) for access to high resolution mass spectrometers and Daniel Kavan and Alan K?dek for help with data processing in the DeutEx software. We thank Grant Hansman (University of Heidelberg, Germany) for providing us with the plasmids of the P domains of GII.4 Saga, GII.10 Vietnam 026 and GII.17 Kawasaki 308. Stefan Taube (University of L?beck, Germany) is thanked for providing the plasmid of the P domain of GII.4 MI001.
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
DFG Research Classification Scheme
- 2.21-04 Virology
