Flexibility and intrinsic disorder are conserved features of hepatitis C virus E2 glycoprotein

Stejskal, L., Lees, W. D., Moss, D. S., Palor, M., Bingham, R. J., Shepherd, A. J. and Grove, J. (2020) Flexibility and intrinsic disorder are conserved features of hepatitis C virus E2 glycoprotein. PLoS Computational Biology, 16(2), e1007710. (doi: 10.1371/journal.pcbi.1007710) (PMID:32109245) (PMCID:PMC7065822)

Abstract

The glycoproteins of hepatitis C virus, E1E2, are unlike any other viral fusion machinery yet described, and are the current focus of immunogen design in HCV vaccine development; thus, making E1E2 both scientifically and medically important. We used pre-existing, but fragmentary, structures to model a complete ectodomain of the major glycoprotein E2 from three strains of HCV. We then performed molecular dynamic simulations to explore the conformational landscape of E2, revealing a number of important features. Despite high sequence divergence, and subtle differences in the models, E2 from different strains behave similarly, possessing a stable core flanked by highly flexible regions, some of which perform essential functions such as receptor binding. Comparison with sequence data suggest that this consistent behaviour is conferred by a network of conserved residues that act as hinge and anchor points throughout E2. The variable regions (HVR-1, HVR-2 and VR-3) exhibit particularly high flexibility, and bioinformatic analysis suggests that HVR-1 is a putative intrinsically disordered protein region. Dynamic cross-correlation analyses demonstrate intramolecular communication and suggest that specific regions, such as HVR-1, can exert influence throughout E2. To support our computational approach we performed small-angle X-ray scattering with purified E2 ectodomain; this data was consistent with our MD experiments, suggesting a compact globular core with peripheral flexible regions. This work captures the dynamic behaviour of E2 and has direct relevance to the interaction of HCV with cell-surface receptors and neutralising antibodies.

• Item Type: Articles
• Additional Information: LS received grant 109162/Z/15/Z from the Wellcome Trust (https://wellcome.ac.uk). JG received grant 107653/Z/15/Z from the Wellcome Trust (https://wellcome.ac.uk) and Royal Society (https://royalsociety.org).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Grove, Dr Joe

Creator Roles

Grove, J.: Conceptualization, Formal analysis, Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review and editing

• Authors: Stejskal, L., Lees, W. D., Moss, D. S., Palor, M., Bingham, R. J., Shepherd, A. J., and Grove, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: PLoS Computational Biology
• Publisher: Public Library of Science
• ISSN: 1553-734X
• ISSN (Online): 1553-7358
• Published Online: 28 February 2020
• Copyright Holders: Copyright © 2020 Stejskal et al.
• First Published: First published in PLoS Computational Biology 16(2): e1007710
• Publisher Policy: Reproduced under a Creative Commons License
• Data DOI: 10.5281/zenodo.3364033