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

DOI: 10.1371/journal.pcbi.1007710 DOI Help

Authors: Lenka Stejskal (University College London (UCL)) , William D. Lees (Birkbeck College, London) , David S. Moss (Birkbeck College, London) , Machaela Palor (University College London) , Richard J. Bingham (University of Huddersfield) , Adrian J. Shepherd (Birkbeck College, London) , Joe Grove (University College London (UCL))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Plos Computational Biology , VOL 16

State: Published (Approved)
Published: February 2020
Diamond Proposal Number(s): 22783

Open Access Open Access

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.

Journal Keywords: Crystal structure; Molecular dynamics; Protein structure comparison; Sequence alignment; Simulation and modeling; Hepatitis C virus; Biochemical simulations; Cysteine

Diamond Keywords: Hepatitis C Virus (HCV); Viruses

Subject Areas: Biology and Bio-materials, Medicine


Instruments: B21-High Throughput SAXS

Added On: 02/04/2020 13:36

Documents:
journal.pcbi.1007710.pdf

Discipline Tags:

Vaccines Pathogens Infectious Diseases Health & Wellbeing Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)