Comparisons of spike proteins from multiple coronaviruses suggest that divergence in the RBM region can account for differences in target receptors, even when the core of the S1 CTD is structurally very similar. There are subtle differences, mainly in the RBM, between the SARS-CoV and SARS-CoV-2 spike proteins' interactions with ACE2. The CTD of these viruses can be further divided into two subdomains, known as the core and the extended loop or receptor-binding motif (RBM), where most of the residues that directly contact the target receptor are located. The CTD is responsible for the interactions of MERS-CoV with its receptor dipeptidyl peptidase-4, and those of SARS-CoV and SARS-CoV-2 with their receptor angiotensin-converting enzyme 2 (ACE2). The NTD has a galectin-like protein fold, but binds sugar molecules somewhat differently than galectins. In general, the NTD binds sugar molecules while the CTD binds proteins, with the exception of mouse hepatitis virus which uses its NTD to interact with a protein receptor called CEACAM1. Target receptors can be very diverse, including cell surface receptor proteins and sugars such as sialic acids as receptors or coreceptors. Depending on the coronavirus, either or both domains may be used as receptor-binding domains (RBD). S1 contains two domains, called the N-terminal domain (NTD) and C-terminal domain (CTD), sometimes also known as the A and B domains. The S1 region of the spike glycoprotein is responsible for interacting with receptor molecules on the surface of the host cell in the first step of viral entry. Each spike protein contains two regions known as S1 and S2, and in the assembled trimer the S1 regions at the N-terminal end form the portion of the protein furthest from the viral surface while the S2 regions form a flexible "stalk" containing most of the protein-protein interactions that hold the trimer in place. The trimer structures have been described as club- pear-, or petal-shaped. Spike glycoprotein forms homotrimers in which three copies of the protein interact through their ectodomains.
It is a single-pass transmembrane protein with a short C-terminal tail on the interior of the virus, a transmembrane helix, and a large N-terminal ectodomain exposed on the virus exterior. The spike protein is very large, often 1200-1400 amino acid residues long it is 1273 residues in SARS-CoV-2. The black bar at the bottom indicates the position of the viral membrane. Helices show in orange and cyan form parts of S2 that will undergo conformational changes during fusion. The S1 NTD is shown in blue and the S1 CTD (which serves as the receptor-binding domain) is shown in pink. Ĭryo-electron microscopy structure of a SARS-CoV-2 spike protein trimer in the pre-fusion conformation, with a single monomer highlighted. Most COVID-19 vaccine development efforts in response to the COVID-19 pandemic aim to activate the immune system against the spike protein.
Neutralizing antibodies target epitopes on the receptor-binding domain. Antibodies against spike glycoprotein are found in patients recovered from SARS and COVID-19. Spike glycoprotein is highly immunogenic. Spike glycoprotein determines the virus' host range (which organisms it can infect) and cell tropism (which cells or tissues it can infect within an organism). The S2 region contains the fusion peptide and other fusion infrastructure necessary for membrane fusion with the host cell, a required step for infection and viral replication. Coronaviruses use a very diverse range of receptors SARS-CoV (which causes SARS) and SARS-CoV-2 (which causes COVID-19) both interact with angiotensin-converting enzyme 2 (ACE2). The S1 region contains the receptor-binding domain that binds to receptors on the cell surface. Spike glycoprotein is a class I fusion protein that contains two regions, known as S1 and S2, responsible for these two functions. The function of the spike glycoprotein is to mediate viral entry into the host cell by first interacting with molecules on the exterior cell surface and then fusing the viral and cellular membranes. The distinctive appearance of these spikes when visualized using negative stain transmission electron microscopy, "recalling the solar corona", gives the virus family its name. The spike protein assembles into trimers that form large structures, called spikes or peplomers, that project from the surface of the virion. Spike (S) glycoprotein (sometimes also called spike protein, formerly known as E2 ) is the largest of the four major structural proteins found in coronaviruses. īetacoronavirus spike glycoprotein S1, receptor bindingīetacoronavirus-like spike glycoprotein S1, N-terminal Model of the external structure of the SARS-CoV-2 virion.
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