7a95
SARS-CoV-2 Spike Glycoprotein with 1 ACE2 Bound and 1 RBD Erect in Clockwise Direction
Structural highlights
FunctionSPIKE_SARS2 attaches the virion to the cell membrane by interacting with host receptor, initiating the infection (By similarity). Binding to human ACE2 receptor and internalization of the virus into the endosomes of the host cell induces conformational changes in the Spike glycoprotein (PubMed:32142651, PubMed:32075877, PubMed:32155444). Uses also human TMPRSS2 for priming in human lung cells which is an essential step for viral entry (PubMed:32142651). Proteolysis by cathepsin CTSL may unmask the fusion peptide of S2 and activate membranes fusion within endosomes.[HAMAP-Rule:MF_04099][1] [2] [3] mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Under the current model, the protein has at least three conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes.[HAMAP-Rule:MF_04099] Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis.[HAMAP-Rule:MF_04099] Publication Abstract from PubMedSARS-CoV-2 infection is initiated by virus binding to ACE2 cell surface receptors(1-4), 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(5-7). 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(8-10). 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(11,12). 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 ACE2 binding events which destabilise the spike trimer, progressively opening up, and out, the individual S1 components. The opening process reduces S1 contacts and un-shields the trimeric S2 core, priming fusion activation and dissociation of ACE2-bound S1 monomers. The structures also reveal refolding of an S1 subdomain following ACE2 binding, that disrupts interactions with S2, notably involving Asp614(13-15), leading to destabilisation of the structure of S2 proximal to the secondary (S2') cleavage site. Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion.,Benton DJ, Wrobel AG, Xu P, Roustan C, Martin SR, Rosenthal PB, Skehel JJ, Gamblin SJ Nature. 2020 Sep 17. pii: 10.1038/s41586-020-2772-0. doi:, 10.1038/s41586-020-2772-0. PMID:32942285[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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