Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core

Pak, Alexander J.; Yu, Alvin; Ke, Zunlong; Briggs, John; Voth, Gregory A.

doi:10.1101/2021.05.24.445443

Cited by 5 publications

(4 citation statements)

References 62 publications

(94 reference statements)

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“…We reveal that the ACE2 binding energy is distributed between both the S1 and S2 subunits. The ACE2 binding to one S1 subunit promotes additional protomers to open in a cooperative manner, in line with previous reports 14,65 , causes rigidification of the RBD-s and the expulsion of the 630 loop from its unbound trimer position, which likely exposes the abutting S1-S2 cleavage site for easier protease cleavage. In the S2 subunit, the FPPR becomes more dynamic likely enabling the fusion peptide to engage the host cell membrane while also exposing the proximal S2′ site for cleavage.…”

Section: Discussionsupporting

confidence: 90%

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

Calvaresi

Wrobel

Toporowska

et al. 2022

Preprint

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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 conformation, 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 emergence.

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Section: Discussionsupporting

confidence: 90%

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

Calvaresi

Wrobel

Toporowska

et al. 2022

Preprint

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“…On the other hand, if locked interfaces act in concert throughout the Omicron S trimer, as appears to be the case for LA-bound S trimer (Toelzer et al, 2020), and with increased locking of the RBD, how would this be consistent with the view that a higher proportion of RBD up correlates directly with ACE2 binding and infectivity? In that case, it is possible that the cooperativity in S protein interaction with ACE2, thought to enhance progression to a fusion competent state (Pak et al, 2021), could play a role. Since locked conformations are more tightly packed between monomers, they could be involved in more cooperative transitions to RBD up (open) forms than would be the more loosely packed closed conformations.…”

Section: Resultsmentioning

confidence: 99%

Relationship between monomer packing, receptor binding domain pocket status, and pH, in the spike trimer of SARS-CoV-2 variants

Warwicker¹

2021

Preprint

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Existence of a SARS-CoV-2 spike protein trimer form with closer packing between monomers when receptor binding domains (RBDs) are all down, locked as opposed to closed, has been associated with linoleic acid (LA) binding at neutral pH, or can occur at acidic pH in the absence of LA binding. The relationship between degree of closure of the LA binding pocket of the RBD, and monomer burial in the trimer, is examined for a range of spike protein structures, including those with D614G mutation, and that of the Delta variant (which also carries D614G). Some spike protein structures with this aspartic acid mutation show monomer packing approaching that of the locked form (at neutral pH, without LA binding) for two segments, a third (around the RBD) remains less closely packed. Analysis of other coronavirus RBD structures suggests that mutation of the RBD in spike protein of the Omicron variant could lead to LA binding pocket changes. It is proposed that these changes could lead to one of two consequences for the Omicron variant spike protein (which also has the D614G mutation), at neutral pH and without LA binding, either easier access to a locked form throughout that leads to cooperative transitions between all RBD down and all RBD up, or maintenance of a spike trimer with locked characteristics C-terminal to the RBD at the same time as the RBD is free to transit between down and up states. The situation may also be impacted by spike protein charge mutations in the Omicron lineage that alter pH-dependence around the RBD, in a similar way to the changes induced elsewhere by D614G.

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“…Mechanistically, the detachment of S1 may serve to accelerate the uncapping of the fusogenic S2 subunit, while enable the insertion of fusion peptide into nearby plasma membranes to initiate the ACE2-independent cell-cell fusion [17,[52][53][54]. It is unclear whether other associated factors, such as lectins, NRP1 and TMEM106B [23,24,55,56], or glycosylation profiles of adjacent residues near the S1/S2 cleavage site [57], affect spike activation and cell-cell fusion.…”

Section: Plos Pathogensmentioning

confidence: 99%

Antibody-mediated spike activation promotes cell-cell transmission of SARS-CoV-2

Yu,

Zheng,

Zhou

et al. 2023

PLoS Pathog

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The COVID pandemic fueled by emerging SARS-CoV-2 new variants of concern remains a major global health concern, and the constantly emerging mutations present challenges to current therapeutics. The spike glycoprotein is not only essential for the initial viral entry, but is also responsible for the transmission of SARS-CoV-2 components via syncytia formation. Spike-mediated cell-cell transmission is strongly resistant to extracellular therapeutic and convalescent antibodies via an unknown mechanism. Here, we describe the antibody-mediated spike activation and syncytia formation on cells displaying the viral spike. We found that soluble antibodies against receptor binding motif (RBM) are capable of inducing the proteolytic processing of spike at both the S1/S2 and S2’ cleavage sites, hence triggering ACE2-independent cell-cell fusion. Mechanistically, antibody-induced cell-cell fusion requires the shedding of S1 and exposure of the fusion peptide at the cell surface. By inhibiting S1/S2 proteolysis, we demonstrated that cell-cell fusion mediated by spike can be re-sensitized towards antibody neutralization in vitro. Lastly, we showed that cytopathic effect mediated by authentic SARS-CoV-2 infection remain unaffected by the addition of extracellular neutralization antibodies. Hence, these results unveil a novel mode of antibody evasion and provide insights for antibody selection and drug design strategies targeting the SARS-CoV-2 infected cells.

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Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core

Cited by 5 publications

References 62 publications

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

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

Relationship between monomer packing, receptor binding domain pocket status, and pH, in the spike trimer of SARS-CoV-2 variants

Antibody-mediated spike activation promotes cell-cell transmission of SARS-CoV-2

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