Coronavirus spike protein

: 6VSB. Only one monomer is highlighted. Whole protein is a homotrimer. Rest of the trimer is shown as a gray surface. Parts of the actual structure are not shown. The following are listed from N-terminal (letter N) to C-terminal (C): N-terminal domain (blue), ACE2 receptor binding domain (magenta) general structure (cyan), central helix (orange, faces inside of the homotrimer) and connector domain (purple, anchors the spike protein to virus lipid envelope). Yellow: disulfide bonds. Red: carbohydrates. Gray block: lipid membrane of the virus. The spike protein is very large, often 1200 to 1400 amino acid residues long; S1 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. Depending on the coronavirus, either or both domains may be used as receptor-binding domains (RBD). Target receptors can be very diverse, including cell surface receptor proteins and sugars such as sialic acids as receptors or coreceptors. and loss of that binding through mutation of the corresponding sugar binding pocket in emergent variants of concern has suggested a potential role for tranisent sugar-binding in the zoonosis of SARS-CoV-2, consistent with prior evolutionary proposals. The CTD is responsible for the interactions of MERS-CoV with its receptor dipeptidyl peptidase-4, Spike glycoprotein is heavily glycosylated through N-linked glycosylation. The C-terminal tail, located in the interior of the virion, is enriched in cysteine residues and is palmitoylated. Spike proteins are activated through proteolytic cleavage. They are cleaved by host cell proteases at the S1-S2 boundary and later at what is known as the S2' site at the N-terminus of the fusion peptide. Functionally important protein dynamics have also been observed within the pre-fusion state, in which the relative orientations of some of the S1 regions relative to S2 in a trimer can vary. In the closed state, all three S1 regions are packed closely and the region that makes contact with host cell receptors is sterically inaccessible, while the open states have one or two S1 RBDs more accessible for receptor binding, in an open or "up" conformation. of a SARS-CoV-2 virion, showing the characteristic "corona" appearance with the spike proteins (green) forming prominent projections from the surface of the virion (yellow). == Expression and localization ==

The gene encoding the spike protein is located toward the 3' end of the virus's positive-sense RNA genome, along with the genes for the other three structural proteins and various virus-specific accessory proteins. , showing the positions of the four structural proteins and components of the extracellular environment. The spike protein is not required for viral assembly or the formation of virus-like particles; Incorporation of the spike protein into virions during assembly and budding is dependent on protein-protein interactions with the M protein through the C-terminal tail. to 100 spike trimers per virion. == Function ==

The spike protein is responsible for viral entry into the host cell, a required early step in viral replication. It is essential for replication. The location of fusion varies depending on the specific coronavirus, with some able to enter at the plasma membrane and others entering from endosomes after endocytosis. The presence of a target receptor that S1 can bind is a determinant of host range and cell tropism. Human serum albumin binds to the S1 region, competing with ACE2 and therefore restricting viral entry into cells. Proteolytic cleavage Proteolytic cleavage of the spike protein, sometimes known as "priming", is required for membrane fusion. Relative to other class I fusion proteins, this process is complex and requires two cleavages at different sites, one at the S1/S2 boundary and one at the S2' site to release the fusion peptide. Trypsin and trypsin-like proteases have also been reported to contribute. and (post-fusion). Like other class I fusion proteins, the spike protein in its pre-fusion conformation is in a metastable state. In vitro studies of SARS-CoV suggest a dependence on calcium concentration. This behavior can be observed in infected cells in cell culture. Syncytia have been observed in patient tissue samples from infections with SARS-CoV, MERS-CoV, and SARS-CoV-2, Immunogenicity Because it is exposed on the surface of the virus, the spike protein is a major antigen to which neutralizing antibodies are developed. Its extensive glycosylation can serve as a glycan shield that hides epitopes from the immune system. or interfere with the process of conformational change. More recently antibodies targeting the S2 subunit of the spike protein have been reported with broad neutralization activities against variants. == COVID-19 response ==

Vaccines In response to the COVID-19 pandemic, a number of COVID-19 vaccines have been developed using a variety of technologies, including mRNA vaccines and viral vector vaccines. Most vaccine development has targeted the spike protein. Building on techniques previously used in vaccine research aimed at respiratory syncytial virus and SARS-CoV, many SARS-CoV-2 vaccine development efforts have used constructs that include mutations to stabilize the spike protein's pre-fusion conformation, facilitating development of antibodies against epitopes exposed in this conformation. Monoclonal antibodies (blue) and imdevimab (orange) interacting with the receptor-binding domain of the spike protein (pink). Monoclonal antibodies that target the receptor-binding domain of the spike protein have been developed as COVID-19 treatments. As of July 8, 2021, three monoclonal antibody products had received Emergency Use Authorization in the United States: bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab. Bamlanivimab/etesevimab was not recommended in the United States due to the increase in SARS-CoV-2 variants that are less susceptible to these antibodies. Many of these possess mutations that change the amino acid sequence of the spike protein. In a World Health Organization analysis from July 2020, the spike (S) gene was the second most frequently mutated in the genome, after ORF1ab (which encodes most of the virus' nonstructural proteins). Analyses of SARS-CoV-2 genomes suggests that some sites in the spike protein sequence, particularly in the receptor-binding domain, are of evolutionary importance and are undergoing positive selection. Spike protein mutations raise concern because they may affect infectivity or transmissibility, or facilitate immune escape. it may have advantages in infectivity and transmissibility increasing the proportion of binding-competent conformations or improving stability, but it does not affect vaccines. The mutation N501Y is common to the Alpha, Beta, Gamma and Omicron Variants of SARS-CoV-2 and has contributed to enhanced infection and transmission, reduced vaccine efficacy, and the ability of SARS-CoV-2 to infect new rodent species. N501Y increases the affinity of spike for human ACE2 by around 10-fold, which could underlie some of fitness advantages conferred by this mutation even though the relationship between affinity and infectivity is complex. The mutation P681R alters the furin cleavage site, and has been responsible for increased infectivity, transmission and global impact of the SARS-CoV-2 Delta variant. Mutations at position E484, particularly E484K, have been associated with immune escape and reduced antibody binding. The SARS CoV-2 spike gene (S gene, S-gene) mutation 69–70del (Δ69-70) causes a TaqPath PCR test probe to not bind to its S gene target, leading to S gene target failure (SGTF) in SARS CoV-2 positive samples. This effect was used as a marker to monitor the propagation of the Alpha variant and the Omicron variant. Misinformation During the COVID-19 pandemic, anti-vaccination misinformation about COVID-19 circulated on social media platforms related to the spike protein's role in COVID-19 vaccines. Spike proteins were said to be dangerously "cytotoxic" and mRNA vaccines containing them therefore in themselves dangerous. Spike proteins are not cytotoxic or dangerous. Spike proteins were also said to be "shed" by vaccinated people, in an erroneous allusion to the phenomenon of vaccine-induced viral shedding, which is a rare effect of live-virus vaccines unlike those used for COVID-19. "Shedding" of spike proteins is not possible. == Evolution, conservation and recombination ==

The class I fusion proteins, a group whose well-characterized examples include the coronavirus spike protein, influenza virus hemagglutinin, and HIV Gp41, are thought to be evolutionarily related. The S2 region of the spike protein responsible for membrane fusion is more highly conserved than the S1 region responsible for receptor interactions. Within the S1 region, the N-terminal domain (NTD) is more conserved than the C-terminal domain (CTD). and in some cases, distantly related coronaviruses that use the same cell-surface receptor may do so through convergent evolution. == References ==