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

Cantoni, D. and Murray, M.J. and Kalemera, M.D. and Dicken, S.J. and Stejskal, Lenka and Brown, G. and Lytras, S. and Coey, J.D. and McKenna, J. and Bridgett, S. and Simpson, D. and Fairley, D. and Thorne, L.G. and Reuschl, A.-K. and Forrest, C. and Ganeshalingham, M. and Muir, L. and Palor, M. and Jarvis, L. and Willett, B. and Power, U.F. and McCoy, L.E. and Jolly, C. and Towers, G.J. and Doores, K.J. and Robertson, D.L. and Shepherd, Adrian and Reeves, M.B. and Bamford, C.G.G and Grove, J. (2022) Evolutionary remodelling of N-terminal domain loops fine-tunes SARS-CoV-2 spike. EMBO reports e54322 , ISSN 1469-221X.

Abstract

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.

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