Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein

Eamonn Reading; Valeria Calvaresi; Dietmar Hammerschmid; Joanna Toporowska; Katherine Doores; Richard T. Bradshaw; Michael Malim; Argyris Politis; Chloe Roustan; Antoni G Wrobel; Steve J Gamblin; Donald J. Benton; Ricardo B  Parsons

Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein

Eamonn Reading, Valeria Calvaresi^*, Dietmar Hammerschmid, Joanna Toporowska, Katherine Doores, Richard T. Bradshaw, Michael Malim, Argyris Politis^*, Chloe Roustan, Antoni G Wrobel^*, Steve J Gamblin, Donald J. Benton, Ricardo B Parsons

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

SARS-CoV-2 spike glycoprotein mediates receptor binding and subsequent
membrane fusion. It exists in a range of conformations, including a closed state
unable to bind the ACE2 receptor, and an open state that does so but displays more
exposed antigenic surface. Spikes of variants of concern (VOCs) acquired amino acid
changes linked to increased virulence and immune evasion. Here, using HDX-MS,
we identified changes in spike dynamics that we associate with the transition from
closed to open conformations, to ACE2 binding, and to specific mutations in VOCs.
We show that the RBD-associated subdomain plays a role in spike opening, whereas
the NTD acts as a hotspot of conformational divergence of VOC spikes driving
immune evasion. Alpha, beta and delta spikes assume predominantly open
conformations and ACE2 binding increases the dynamics of their core helices,
priming spikes for fusion. Conversely, substitutions in omicron spike lead to
predominantly closed conformations, presumably enabling it to escape antibodies. At
the same time, its core helices show characteristics of being pre-primed for fusion
even in the absence of ACE2. These data inform on SARS-CoV-2 evolution and
omicron variant emergence.

Original language	English
Journal	Nature Communications
Publication status	Accepted/In press - 15 Feb 2023

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@article{9349805123684012bdabd1ff252d0099,

title = "Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein",

abstract = "SARS-CoV-2 spike glycoprotein mediates receptor binding and subsequentmembrane fusion. It exists in a range of conformations, including a closed stateunable to bind the ACE2 receptor, and an open state that does so but displays moreexposed antigenic surface. Spikes of variants of concern (VOCs) acquired amino acidchanges linked to increased virulence and immune evasion. Here, using HDX-MS,we identified changes in spike dynamics that we associate with the transition fromclosed to open conformations, to ACE2 binding, and to specific mutations in VOCs.We show that the RBD-associated subdomain plays a role in spike opening, whereasthe NTD acts as a hotspot of conformational divergence of VOC spikes drivingimmune evasion. Alpha, beta and delta spikes assume predominantly openconformations and ACE2 binding increases the dynamics of their core helices,priming spikes for fusion. Conversely, substitutions in omicron spike lead topredominantly closed conformations, presumably enabling it to escape antibodies. Atthe same time, its core helices show characteristics of being pre-primed for fusioneven in the absence of ACE2. These data inform on SARS-CoV-2 evolution andomicron variant emergence.",

author = "Eamonn Reading and Valeria Calvaresi and Dietmar Hammerschmid and Joanna Toporowska and Katherine Doores and Bradshaw, {Richard T.} and Michael Malim and Argyris Politis and Chloe Roustan and Wrobel, {Antoni G} and Gamblin, {Steve J} and Benton, {Donald J.} and Parsons, {Ricardo B}",

year = "2023",

month = feb,

day = "15",

language = "English",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein

AU - Reading, Eamonn

AU - Calvaresi, Valeria

AU - Hammerschmid, Dietmar

AU - Toporowska, Joanna

AU - Doores, Katherine

AU - Bradshaw, Richard T.

AU - Malim, Michael

AU - Politis, Argyris

AU - Roustan, Chloe

AU - Wrobel, Antoni G

AU - Gamblin, Steve J

AU - Benton, Donald J.

AU - Parsons, Ricardo B

PY - 2023/2/15

Y1 - 2023/2/15

N2 - SARS-CoV-2 spike glycoprotein mediates receptor binding and subsequentmembrane fusion. It exists in a range of conformations, including a closed stateunable to bind the ACE2 receptor, and an open state that does so but displays moreexposed antigenic surface. Spikes of variants of concern (VOCs) acquired amino acidchanges linked to increased virulence and immune evasion. Here, using HDX-MS,we identified changes in spike dynamics that we associate with the transition fromclosed to open conformations, to ACE2 binding, and to specific mutations in VOCs.We show that the RBD-associated subdomain plays a role in spike opening, whereasthe NTD acts as a hotspot of conformational divergence of VOC spikes drivingimmune evasion. Alpha, beta and delta spikes assume predominantly openconformations and ACE2 binding increases the dynamics of their core helices,priming spikes for fusion. Conversely, substitutions in omicron spike lead topredominantly closed conformations, presumably enabling it to escape antibodies. Atthe same time, its core helices show characteristics of being pre-primed for fusioneven in the absence of ACE2. These data inform on SARS-CoV-2 evolution andomicron variant emergence.

AB - SARS-CoV-2 spike glycoprotein mediates receptor binding and subsequentmembrane fusion. It exists in a range of conformations, including a closed stateunable to bind the ACE2 receptor, and an open state that does so but displays moreexposed antigenic surface. Spikes of variants of concern (VOCs) acquired amino acidchanges linked to increased virulence and immune evasion. Here, using HDX-MS,we identified changes in spike dynamics that we associate with the transition fromclosed to open conformations, to ACE2 binding, and to specific mutations in VOCs.We show that the RBD-associated subdomain plays a role in spike opening, whereasthe NTD acts as a hotspot of conformational divergence of VOC spikes drivingimmune evasion. Alpha, beta and delta spikes assume predominantly openconformations and ACE2 binding increases the dynamics of their core helices,priming spikes for fusion. Conversely, substitutions in omicron spike lead topredominantly closed conformations, presumably enabling it to escape antibodies. Atthe same time, its core helices show characteristics of being pre-primed for fusioneven in the absence of ACE2. These data inform on SARS-CoV-2 evolution andomicron variant emergence.

M3 - Article

SN - 2041-1723

JO - Nature Communications

JF - Nature Communications

ER -

Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein

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