Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is initiated by virus binding to the ACE2 cell-surface receptors 1 – 4 , followed by fusion of the virus and cell membranes to release the virus genome into the cell. Both receptor binding and membrane fusion activities are...

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Vydané v:	Nature (London) Ročník 588; číslo 7837; s. 327 - 330
Hlavní autori:	Benton, Donald J., Wrobel, Antoni G., Xu, Pengqi, Roustan, Chloë, Martin, Stephen R., Rosenthal, Peter B., Skehel, John J., Gamblin, Steven J.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 10.12.2020 Nature Publishing Group
Predmet:	101/28 631/326/596/4130 631/535/1258/1259 82/80 ACE2 Angiotensin-converting enzyme 2 Angiotensin-Converting Enzyme 2 - chemistry Angiotensin-Converting Enzyme 2 - metabolism Angiotensin-Converting Enzyme 2 - ultrastructure Binding Binding sites Binding sites (Biochemistry) Cell membranes Cell receptors Cell surface Cleavage Coronaviruses COVID-19 Cryoelectron Microscopy Destabilization Dissociation Electron microscopy Furin Furin - metabolism Fusion protein Genomes Glycoproteins Health aspects Humanities and Social Sciences Humans Membrane fusion Membrane Fusion - physiology Membrane proteins Membranes Microscopy Models, Molecular Monomers multidisciplinary Observations Peptides Physiological aspects Post-translation Priming Protein Binding Protein Folding Protein Subunits - chemistry Protein Subunits - metabolism Proteins Proteolysis Receptors Receptors, Coronavirus - chemistry Receptors, Coronavirus - metabolism Receptors, Coronavirus - ultrastructure Science Science (multidisciplinary) Severe acute respiratory syndrome coronavirus 2 Species classification Spike Glycoprotein, Coronavirus - chemistry Spike Glycoprotein, Coronavirus - metabolism Spike Glycoprotein, Coronavirus - ultrastructure Spike protein Trimers Viral diseases Viral proteins Viruses United Kingdom
ISSN:	0028-0836, 1476-4687, 1476-4687
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Shrnutí:	Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is initiated by virus binding to the ACE2 cell-surface receptors 1 – 4 , followed by fusion of the 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 5 – 7 . As with other class-I membrane-fusion proteins, the spike protein is post-translationally cleaved, in this case by furin, into the S1 and S2 components that remain associated after cleavage 8 – 10 . Fusion activation after receptor binding is proposed to involve the exposure of a second proteolytic site (S2′), cleavage of which is required for the release of the fusion peptide 11 , 12 . Here we analyse the binding of ACE2 to the furin-cleaved form of the SARS-CoV-2 spike protein using cryo-electron microscopy. 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 ACE2-binding events that destabilize the spike trimer, progressively opening up, and out, the individual S1 components. The opening process reduces S1 contacts and unshields the trimeric S2 core, priming the protein for fusion activation and dissociation of ACE2-bound S1 monomers. The structures also reveal refolding of an S1 subdomain after ACE2 binding that disrupts interactions with S2, which involves Asp614 13 – 15 and leads to the destabilization of the structure of S2 proximal to the secondary (S2′) cleavage site. Cryo-electron microscopy structures of consecutive binding events of ACE2 in complex with the spike protein of SARS-CoV-2 reveal the mechanisms of receptor binding by the spike protein and activation for membrane fusion by the spike protein of SARS-CoV-2.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-020-2772-0