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

Diego Cantoni, Matthew J. Murray, Mphatso D. Kalemera, Samuel J. Dicken, Lenka Stejskal, Georgina Brown, Spyros Lytras, Jonathon D. Coey, James McKenna, Stephen Bridgett, David Simpson, Derek Fairley, Lucy G. Thorne, Ann Kathrin Reuschl, Calum Forrest, Maaroothen Ganeshalingham, Luke Muir, Machaela Palor, Lisa Jarvis, Brian WillettUltan F. Power, Laura E. McCoy, Clare Jolly, Greg J. Towers, Katie J. Doores, David L. Robertson, Adrian J. Shepherd, Matthew B. Reeves, Connor G.G. Bamford, Joe Grove*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)


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.

Original languageEnglish
Article numbere54322
JournalEMBO Reports
Issue number10
Publication statusPublished - 6 Oct 2022


  • NTD
  • SARS-CoV-2
  • spike
  • variants


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