Evolutionary remodelling of N-terminal domain loops fine-tunes SARS-CoV-2 spike

Cantoni, D. et al. (2022) Evolutionary remodelling of N-terminal domain loops fine-tunes SARS-CoV-2 spike. EMBO Reports, 23(10), e54322. (doi: 10.15252/embr.202154322) (PMID:35999696) (PMCID:PMC9535765)

[img] Text
277406.pdf - Published Version
Available under License Creative Commons Attribution.



The emergence of SARS-CoV-2 variants has exacerbated the COVID-19 global health crisis. Thus far, all variants carry mutations in the spike glycoprotein, which is a critical determinant of viral transmission being responsible for attachment, receptor engagement and membrane fusion, and an important target of immunity. Variants frequently bear truncations of flexible loops in the N-terminal domain (NTD) of spike; the functional importance of these modifications has remained poorly characterised. We demonstrate that NTD deletions are important for efficient entry by the Alpha and Omicron variants and that this correlates with spike stability. Phylogenetic analysis reveals extensive NTD loop length polymorphisms across the sarbecoviruses, setting an evolutionary precedent for loop remodelling. Guided by these analyses, we demonstrate that variations in NTD loop length, alone, are sufficient to modulate virus entry. We propose that variations in NTD loop length act to fine-tune spike; this may provide a mechanism for SARS-CoV-2 to navigate a complex selection landscape encompassing optimisation of essential functionality, immune driven antigenic variation and ongoing adaptation to a new host.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Grove, Dr Joe and Robertson, Professor David and Willett, Professor Brian and Bamford, Dr Connor and Cantoni, Dr Diego and Lytras, Spyros
Authors: Cantoni, D., Murray, M. J., Kalemera, M. D., Dicken, S. J., Stejskal, L., Brown, G., Lytras, S., Coey, J. D., McKenna, J., Bridgett, S., Simpson, D., Fairley, D., Thorne, L. G., Reuschl, A.-K., Forrest, C., Ganeshalingham, M., Muir, L., Palor, M., Jarvis, L., Willett, B., Power, U. F., McCoy, L. E., Jolly, C., Towers, G. J., Doores, K. J., Robertson, D. L., Shepherd, A. J., Reeves, M. B., Bamford, C. G.G., and Grove, J.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:EMBO Reports
ISSN (Online):1469-3178
Published Online:23 August 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in EMBO Reports 23(10): e54322
Publisher Policy:Reproduced under a Creative Commons License

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
316100Studying hepatitis C virus to determine how viruses harness structural disorder to control entry and antibody resistance.Joseph GroveWellcome Trust (WELLCOTR)107653/A/15/ZIII - Centre for Virus Research
315250MRC PE seed funding - John McLauchlanJohn McLauchlanMedical Research Council (MRC)MC_UU_12014III - Centre for Virus Research