Rare driver mutations in head and neck squamous cell carcinomas converge on NOTCH signaling

Loganathan, Sampath K.; Schleicher, Krista; Malik, Ahmad; Quevedo, Rene; Langille, Ellen; Teng, Katie; Oh, Robin H.; Rathod, Bhavisha; Tsai, Ricky; Samavarchi-Tehrani, Payman; Pugh, Trevor J.; Gingras, Anne‐Claude; Schramek, Daniel

doi:10.1126/science.aax0902

Cited by 238 publications

(248 citation statements)

References 50 publications

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“…1a). The overall structure of the closed conformation of the S trimer is three-fold symmetric and similar to structures described previously using uncleaved material2, 16 (Fig. 1a).…”

supporting

confidence: 81%

Evolution of SARS-CoV-2 spike glycoprotein

Wrobel

Benton

et al. 2020

Preprint

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The spike glycoprotein (S) of SARS-CoV-2 mediates attachment of the virus to cell surface receptors and fusion between virus and cell membranes1. The receptor for SARS-CoV-2, like that for SARS-CoV, is the human cell-surface membrane protein ACE22–4. Membrane fusion activity, as for other class-1 fusion glycoproteins, requires S to be proteolytically cleaved into S1 and S2 that remain associated following cleavage4–7. SARS-CoV-2 is thought to have emerged from bats, possibly via a secondary host8,9. To better understand the transmission of SARS-CoV-2 we have determined the structure of its furin-cleaved S by cryoEM, which shows that cleavage at this polybasic amino-acid site increases the structural plasticity of the receptor binding region and facilitates the adoption of an open conformation that is required for it to bind to the ACE2 receptor. To investigate relationships between S proteins of SARS-CoV-2 and of the most closely related bat virus, RaTG138, we have determined and compared their structures and characterised biochemically their affinities for ACE2 and their relative stabilities. Whilst the overall structures are similar, there are key differences likely pertinent to virus infectivity. These include a more stable pre-cleavage form of human S, about 1000-fold tighter binding of SARS-CoV-2 to human receptor, and a higher proportion of S in the conformation required for binding ACE2 upon protease cleavage.

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“…1a). The overall structure of the closed conformation of the S trimer is three-fold symmetric and similar to structures described previously using uncleaved material2, 16 (Fig. 1a).…”

supporting

confidence: 81%

Evolution of SARS-CoV-2 spike glycoprotein

Wrobel

Benton

et al. 2020

Preprint

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“…A recent crystal structure 5 of the complex of the SARS-CoV-2 RBD and the Fab of CR3022 indicates that the antibody binds to a conserved region of the RBD, which does not overlap with the receptor-binding surface. Trimeric S on the virus surface is thought to adopt two main conformations: closed, in which much of the RBD surface is buried inside the trimer and unable to bind the receptor ACE2, and open, in which one RBD protrudes from the trimer and can bind the receptor 6,7 . Neither of these conformations is able to accommodate the binding of CR3022.…”

Section: Full Textmentioning

confidence: 99%

Antibody-mediated disruption of the SARS-CoV-2 spike glycoprotein

Wrobel

Benton

Hussain

et al. 2020

Preprint

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“…Each S1 component consists of two large domains, the N-terminal domain (NTD) and receptor-binding domain (RBD), each associated with a smaller intermediate subdomain. In virus membranes, Spike glycoproteins exist in a closed form, in which the RBDs cap the top of the S2 core and are inaccessible to ACE2, and in an open form, in which one S1 component has opened to expose the RBD for ACE2 binding6, 16,18,22. Recent structural studies on the isolated RBD of SARS-CoV-2 S in complex with ACE27,23,24 provided a molecular description of the interface.…”

Section: Main Textmentioning

confidence: 99%

Sequential receptor binding primes the SARS-CoV-2 S glycoprotein for membrane fusion

Benton¹,

Wrobel²,

et al. 2020

Preprint

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SARS-CoV-2 infection is initiated by virus binding to ACE2 cell surface receptors, followed by fusion of virus and cell membranes to release the virus genome into the cell. Both receptor binding and membrane fusion activities are mediated by the virus spike glycoprotein, S. As with other class I membrane fusion proteins, S is post-translationally cleaved, in this case by furin, into S1 and S2 components that remain associated following cleavage. Fusion activation following receptor binding is proposed to involve the exposure of a second proteolytic site (S2’), cleavage of which is required for the fusion peptide release. We have investigated the binding of ACE2 to the furin-cleaved form of SARS-CoV-2 S by cryoEM. We classify ten different molecular species including the unbound, closed spike trimer, the fully open ACE2-bound trimer, and dissociated monomeric S1 bound to ACE2. The ten structures describe sequential ACE2 binding events which destabilise the spike trimer, progressively opening up, and out, the individual S1 components. The opening process reduces S1 contacts with each other and un-shields the trimeric S2 core, priming fusion activation and dissociation of ACE2-bound S1 monomers. The structures also reveal refolding of one of the S1 subdomains, following ACE2 binding, that disrupts interactions with S2, notably involving Asp614, leading to destabilisation of the structure of S2 proximal to the secondary (S2’) cleavage site.

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Rare driver mutations in head and neck squamous cell carcinomas converge on NOTCH signaling

Cited by 238 publications

References 50 publications

Evolution of SARS-CoV-2 spike glycoprotein

Evolution of SARS-CoV-2 spike glycoprotein

Antibody-mediated disruption of the SARS-CoV-2 spike glycoprotein

Sequential receptor binding primes the SARS-CoV-2 S glycoprotein for membrane fusion

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