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Evolutionary remodelling of N-terminal domain loops fine-tunes SARS-CoV-2 spike.
EMBO Rep. 2022 10 06; 23(10):e54322.ER

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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Authors+Show Affiliations

Cantoni D
MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, UK.
Murray MJ
Division of Infection and Immunity, University College London, London, UK.
Kalemera MD
Division of Infection and Immunity, University College London, London, UK.
Dicken SJ
Division of Infection and Immunity, University College London, London, UK.
Stejskal L
Division of Evolution, Infection and Genomics, University of Manchester, Manchester, UK.
Brown G
Division of Infection and Immunity, University College London, London, UK.
Lytras S
MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, UK.
Coey JD
Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
McKenna J
Belfast Health and Social Care Trust, Belfast, UK.
Bridgett S
Belfast Health and Social Care Trust, Belfast, UK.
Simpson D
Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
Fairley D
Belfast Health and Social Care Trust, Belfast, UK.
Thorne LG
Division of Infection and Immunity, University College London, London, UK.
Reuschl AK
Division of Infection and Immunity, University College London, London, UK.
Forrest C
Division of Infection and Immunity, University College London, London, UK.
Ganeshalingham M
Division of Infection and Immunity, University College London, London, UK.
Muir L
Division of Infection and Immunity, University College London, London, UK.
Palor M
Division of Infection and Immunity, University College London, London, UK.
Jarvis L
Scottish National Blood Transfusion Service, Glasgow, UK.
Willett B
MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, UK.
Power UF
Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
McCoy LE
Division of Infection and Immunity, University College London, London, UK.
Jolly C
Division of Infection and Immunity, University College London, London, UK.
Towers GJ
Division of Infection and Immunity, University College London, London, UK.
Doores KJ
Department of Infectious Diseases, King's College London, London, UK.
Robertson DL
MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, UK.
Shepherd AJ
Department of Biological Sciences, Birkbeck College London, London, UK.
Reeves MB
Division of Infection and Immunity, University College London, London, UK.
Bamford CGG
Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
Grove J
MRC-University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow, UK. Division of Infection and Immunity, University College London, London, UK.

MeSH

COVID-19HumansPhylogenySARS-CoV-2Spike Glycoprotein, Coronavirus

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

35999696

Citation

Cantoni, Diego, et al. "Evolutionary Remodelling of N-terminal Domain Loops Fine-tunes SARS-CoV-2 Spike." EMBO Reports, vol. 23, no. 10, 2022, pp. e54322.
Cantoni D, Murray MJ, Kalemera MD, et al. Evolutionary remodelling of N-terminal domain loops fine-tunes SARS-CoV-2 spike. EMBO Rep. 2022;23(10):e54322.
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., ... Grove, J. (2022). Evolutionary remodelling of N-terminal domain loops fine-tunes SARS-CoV-2 spike. EMBO Reports, 23(10), e54322. https://doi.org/10.15252/embr.202154322
Cantoni D, et al. Evolutionary Remodelling of N-terminal Domain Loops Fine-tunes SARS-CoV-2 Spike. EMBO Rep. 2022 10 6;23(10):e54322. PubMed PMID: 35999696.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evolutionary remodelling of N-terminal domain loops fine-tunes SARS-CoV-2 spike. AU - Cantoni,Diego, AU - Murray,Matthew J, AU - Kalemera,Mphatso D, AU - Dicken,Samuel J, AU - Stejskal,Lenka, AU - Brown,Georgina, AU - Lytras,Spyros, AU - Coey,Jonathon D, AU - McKenna,James, AU - Bridgett,Stephen, AU - Simpson,David, AU - Fairley,Derek, AU - Thorne,Lucy G, AU - Reuschl,Ann-Kathrin, AU - Forrest,Calum, AU - Ganeshalingham,Maaroothen, AU - Muir,Luke, AU - Palor,Machaela, AU - Jarvis,Lisa, AU - Willett,Brian, AU - Power,Ultan F, AU - McCoy,Laura E, AU - Jolly,Clare, AU - Towers,Greg J, AU - Doores,Katie J, AU - Robertson,David L, AU - Shepherd,Adrian J, AU - Reeves,Matthew B, AU - Bamford,Connor G G, AU - Grove,Joe, Y1 - 2022/09/01/ PY - 2022/08/02/revised PY - 2021/11/12/received PY - 2022/08/17/accepted PY - 2022/8/25/pubmed PY - 2022/10/12/medline PY - 2022/8/24/entrez KW - NTD KW - SARS-CoV-2 KW - spike KW - variants SP - e54322 EP - e54322 JF - EMBO reports JO - EMBO Rep VL - 23 IS - 10 N2 - 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. SN - 1469-3178 UR - https://www.unboundmedicine.com/medline/citation/35999696/Evolutionary_remodelling_of_N_terminal_domain_loops_fine_tunes_SARS_CoV_2_spike_ DB - PRIME DP - Unbound Medicine ER -