Abstract
SARS-CoV-2 is thought to have emerged from bats, possibly via a secondary host. Here, we investigate the relationship of spike (S) glycoprotein from SARS-CoV-2 with the S protein of a closely related bat virus, RaTG13. We determined cryo-EM structures for RaTG13 S and for both furin-cleaved and uncleaved SARS-CoV-2 S; we compared these with recently reported structures for uncleaved SARS-CoV-2 S. We also biochemically characterized their relative stabilities and affinities for the SARS-CoV-2 receptor ACE2. Although the overall structures of human and bat virus S proteins are similar, there are key differences in their properties, including a more stable precleavage form of human S and about 1,000-fold tighter binding of SARS-CoV-2 to human receptor. These observations suggest that cleavage at the furin-cleavage site decreases the overall stability of SARS-CoV-2 S and facilitates the adoption of the open conformation that is required for S to bind to the ACE2 receptor.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin-Converting Enzyme 2
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Animals
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Betacoronavirus / genetics*
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Betacoronavirus / metabolism
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Betacoronavirus / ultrastructure
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Binding Sites
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COVID-19
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Chiroptera / virology
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Coronavirus Infections / virology
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Cryoelectron Microscopy
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Evolution, Molecular
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Furin / chemistry
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Gene Expression
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HEK293 Cells
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Host-Pathogen Interactions / genetics*
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Humans
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Models, Molecular
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Pandemics
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Peptidyl-Dipeptidase A / chemistry*
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Peptidyl-Dipeptidase A / genetics
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Peptidyl-Dipeptidase A / metabolism
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Pneumonia, Viral / virology
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Protein Binding
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Protein Conformation, alpha-Helical
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Protein Conformation, beta-Strand
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Protein Interaction Domains and Motifs
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Protein Isoforms / chemistry
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Stability
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Proteolysis
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Receptors, Virus / chemistry*
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Receptors, Virus / genetics
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Receptors, Virus / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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SARS-CoV-2
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Spike Glycoprotein, Coronavirus / chemistry*
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Spike Glycoprotein, Coronavirus / genetics
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Spike Glycoprotein, Coronavirus / metabolism
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Structural Homology, Protein
Substances
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Protein Isoforms
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Receptors, Virus
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Recombinant Proteins
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Spike Glycoprotein, Coronavirus
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spike protein, SARS-CoV-2
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Peptidyl-Dipeptidase A
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ACE2 protein, human
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Angiotensin-Converting Enzyme 2
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Furin