Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

Abstract

Graphical AbstractHighlights d SARS-CoV-2 uses ACE2 to enter target cells d SARS-CoV-2 and SARS-CoV bind with similar affinities to ACE2 d Structures of SARS-CoV-2 spike glycoprotein in two conformations d SARS-CoV polyclonal antibodies inhibit SARS-CoV-2 spikemediated entry into cellsIn Brief SARS-CoV-2, a newly emerged pathogen spreading worldwide, binds with high affinity to human ACE2 and uses it as an entry receptor to invade target cells.Cryo-EM structures of the SARS-CoV-2 spike glycoprotein in two distinct conformations, along with inhibition of spike-mediated entry by SARS-CoV polyclonal antibodies, provide a blueprint for the design of vaccines and therapeutics. SUMMARYThe emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S 1 /S 2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.

COVID-19 pathophysiology: A review

“…Human (30). Structural and functional analysis showed that the spike for SARS-CoV-2 also bound to ACE2 (31)(32)(33). ACE2 expression was high in lung, heart, ileum, kidney and bladder (34).…”

“…A two-step sequential protease cleavage to activate spike protein of SARS-CoV and MERS-CoV was proposed as a model, consisting of cleavage at the S1/S2 cleavage site for priming and a cleavage for activation at the S'2 site, a position adjacent to a fusion peptide within the S 2 subunit (35-37). After the cleavage at the S1/S2 cleavage site, S 1 and S 2 subunits remain noncovalently bound and the distal S 1 subunit contributes to the stabilization of the membraneanchored S 2 subunit at the prefusion state (32). Subsequent cleavage at the S'2 site presumably activates the spike for membrane fusion via irreversible, conformational changes.…”

“…The characteristics unique to SARS-CoV-2 among coronaviruses is the existence of furin cleavage site ("RPPA" sequence) at the S1/S2 site. The S1/S2 site of SARS-CoV-2 was entirely subjected to cleavage during biosynthesis in a drastic contrast to SARS-CoV spike, which was incorporated into assembly without cleavage (32). Although the S1/S2 site was also subjected to cleavage by other proteases such as transmembrane protease serine 2 (TMPRSS2) and cathepsin L (37, 39), the ubiquitous expression of furin likely makes this virus very pathogenic.…”

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): An overview of viral structure and host response

“…This glycoprotein is cleaved by the host cell furin-like protease into 2 sub units namely S1 and S2. Part S1 is responsible for the determination of the host virus range and cellular tropism with the receptor binding domain make-up while S2 functions to mediate virus fusion in transmitting host cells [3,10,11].…”

“…This attachment occurs in the binding domain of S protein of SARS-CoV-2 receptors which are present at 331 to 524 residues, and can bind strongly to human ACE2 and bat ACE2 [13]. The entry and binding processes are then followed by fusion of the viral membrane and host cell [11] After fusion occurs, the type II transmembrane serine protease (TMPRSS2) that is present on the surface of the host cell will clear the ACE2 and activate the receptor-attached spike-like, S proteins [15].…”