Spike Glycoprotein-Mediated Entry of SARS Coronaviruses

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 are enveloped, positive-sense, single-stranded RNA viruses and causes of epidemic diseases that have resulted in public health emergencies worldwide. Angiotensin-converting enzyme 2 (ACE2) is the receptor that allows the entry of these two viruses into host cells, a key step in the life cycle of the pathogens. The characterization of the interactions of ACE2 with the viral spike glycoproteins and structural studies of the ACE2-binding-induced conformational changes in the viral spike glycoproteins have furthered our understanding of the entry processes of these two viruses, and these studies provide useful information that will facilitate the development of antiviral agents and vaccines to control the diseases.

Keywords: COVID-19; SARS coronaviruses; conformational change; entry; membrane fusion; receptor binding; spike glycoprotein.

Figure 1

Domain organization and pre-fusion structure of the severe acute respiratory syndrome coronavirus (SARS-CoV) spike (S) protein. (a) A schematic diagram showing the primary sequence and domain organization of the SARS-CoV S protein. The domains and subunits of S are indicated and highlighted with different colors. Domains not shown in the 3D structure (in panel b) are colored white. SS, signal sequence; NTD, N-terminal domain; CTD1/2/3, C-terminal domains 1/2/3; RBD: receptor binding domain; S1/S2: S1/S2 protease cleavage site; S2′: S2′ protease cleavage site; FP: fusion peptide; HR1: heptad repeat 1; CD: connector domain; HR2: heptad repeat 2; TM: transmembrane domain; CT: cytoplasmic tail. (b) Left panel: Pre-fusion structure of the SARS-CoV S protein trimer with one RBD in the “up” conformation shown in side view and top view. The protomer with the “up” RBD is shown in ribbons colored as in the schematic diagram (panel a). The other two protomers with the “down” RBDs are colored black and gray. Right panel: Ribbon diagrams showing one RBD “down” protomer and one RBD “up” protomer.

Figure 2

A cartoon representation of the SARS-CoV S glycoprotein-mediated membrane fusion process. Only the “up” RBD is able to bind the angiotensin-converting enzyme 2 (ACE2) receptor, and ACE2 binding promotes the dissociation of the S1 subunits from the trimer spike. Dissociation of the S1 subunits exposes the S2′ cleavage sites and may lead to the extension of S2 subunits and release of the fusion peptide. After the insertion of the fusion peptides into host cell membrane, the α-helical heptad repeat (HR1) regions of the S2 protomers fold back to interact with the HR2 regions to drive the approach of viral and cell membranes. The folded HR1s then interact with HR2s to form a six-helix bundle that brings the viral membrane and host cell membrane close enough to let the membrane fusion happen.