Coronavirus spike protein#S2

File:6VSB spike protein SARS-CoV-2 monomer in homotrimer.png: [https://www.rcsb.org/structure/6VSB 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; it is 1273 residues in SARS-CoV-2. 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.

Spike glycoprotein forms homotrimers in which three copies of the protein interact through their ectodomains. The trimer structures have been described as club- pear-, or petal-shaped. 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.

{{Infobox protein family

| class =

| Symbol = bCoV_S1_RBD

| Name = Betacoronavirus spike glycoprotein S1, receptor binding

| Pfam = PF09408

| InterPro = IPR018548

}}

{{Infobox protein family

| class =

| Symbol = bCoV_S1_N

| Name = Betacoronavirus-like spike glycoprotein S1, N-terminal

| Pfam = PF16451

| InterPro = IPR032500

}}

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. S1 contains two domains, called the N-terminal domain (NTD) and C-terminal domain (CTD), sometimes also known as the A and B domains.{{cite journal |last1=Hulswit |first1=R.J.G. |last2=de Haan |first2=C.A.M. |last3=Bosch |first3=B.-J. |title=Coronavirus Spike Protein and Tropism Changes |journal=Advances in Virus Research |date=2016 |volume=96 |pages=29–57 |doi=10.1016/bs.aivir.2016.08.004|pmid=27712627 |pmc=7112277 |isbn=978-0-12-804736-1 }} 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. 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. The NTD has a galectin-like protein fold, but binds sugar molecules somewhat differently than galectins. The observed binding of N-acetylneuraminic acid by the NTD{{Cite journal |last1=Buchanan |first1=Charles J. |last2=Gaunt |first2=Ben |last3=Harrison |first3=Peter J. |last4=Yang |first4=Yun |last5=Liu |first5=Jiwei |last6=Khan |first6=Aziz |last7=Giltrap |first7=Andrew M. |last8=Le Bas |first8=Audrey |last9=Ward |first9=Philip N. |last10=Gupta |first10=Kapil |last11=Dumoux |first11=Maud |last12=Tan |first12=Tiong Kit |last13=Schimaski |first13=Lisa |last14=Daga |first14=Sergio |last15=Picchiotti |first15=Nicola |title=Pathogen-sugar interactions revealed by universal saturation transfer analysis |url=https://www.science.org/doi/10.1126/science.abm3125 |journal=Science |date=2022 |language=en |volume=377 |issue=6604 |pages=eabm3125 |doi=10.1126/science.abm3125 |pmid=35737812 |hdl=1983/355cbd8f-c424-4cc0-adb2-881c04ab3bf0 |issn=0036-8075|hdl-access=free }} 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.{{Cite journal |last=Rossmann |first=M G |date=1989 |title=The Canyon Hypothesis |journal=Journal of Biological Chemistry |volume=264 |issue=25 |pages=14587–14590 |doi=10.1016/s0021-9258(18)63732-9 |issn=0021-9258|doi-access=free }}

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 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. There are subtle differences, mainly in the RBM, between the SARS-CoV and SARS-CoV-2 spike proteins' interactions with ACE2. 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.

Within coronavirus lineages, as well as across the four major coronavirus subgroups, the S1 region is less well conserved than S2, as befits its role in interacting with virus-specific host cell receptors. Within the S1 region, the NTD is more highly conserved than the CTD.

{{Infobox protein family

| class =

| Symbol = CoV_S2

| Name = Coronavirus spike glycoprotein S2

| Pfam = PF01601

| InterPro = IPR002552

}}

The S2 region of spike glycoprotein is responsible for membrane fusion between the viral envelope and the host cell, enabling entry of the virus' genome into the cell. The S2 region contains the fusion peptide, a stretch of mostly hydrophobic amino acids whose function is to enter and destabilize the host cell membrane. S2 also contains two heptad repeat subdomains known as HR1 and HR2, sometimes called the "fusion core" region. These subdomains undergo dramatic conformational changes during the fusion process to form a six-helix bundle, a characteristic feature of the class I fusion proteins. The S2 region is also considered to include the transmembrane helix and C-terminal tail located in the interior of the virion.

Relative to S1, the S2 region is very well conserved among coronaviruses.

File:S-protein sugar coat.png.{{cite news |last1=Zimmer |first1=Carl |title=The Coronavirus Unveiled |url=https://www.nytimes.com/interactive/2020/health/coronavirus-unveiled.html |access-date=12 August 2021 |work=The New York Times |date=9 October 2020}}{{cite journal |last1=Casalino |first1=Lorenzo |last2=Gaieb |first2=Zied |last3=Goldsmith |first3=Jory A. |last4=Hjorth |first4=Christy K. |last5=Dommer |first5=Abigail C. |last6=Harbison |first6=Aoife M. |last7=Fogarty |first7=Carl A. |last8=Barros |first8=Emilia P. |last9=Taylor |first9=Bryn C. |last10=McLellan |first10=Jason S. |last11=Fadda |first11=Elisa |last12=Amaro |first12=Rommie E. |title=Beyond Shielding: The Roles of Glycans in the SARS-CoV-2 Spike Protein |journal=ACS Central Science |date=28 October 2020 |volume=6 |issue=10 |pages=1722–1734 |doi=10.1021/acscentsci.0c01056|pmid=33140034 |pmc=7523240 }}]]

Spike glycoprotein is heavily glycosylated through N-linked glycosylation. Studies of the SARS-CoV-2 spike protein have also reported O-linked glycosylation in the S1 region.{{cite journal |last1=Shajahan |first1=Asif |last2=Supekar |first2=Nitin T |last3=Gleinich |first3=Anne S |last4=Azadi |first4=Parastoo |title=Deducing the N- and O-glycosylation profile of the spike protein of novel coronavirus SARS-CoV-2 |journal=Glycobiology |date=9 December 2020 |volume=30 |issue=12 |pages=981–988 |pmid=32363391 |pmc=7239183 |doi=10.1093/glycob/cwaa042}} The C-terminal tail, located in the interior of the virion, is enriched in cysteine residues and is palmitoylated.{{cite journal |last1=Ujike |first1=Makoto |last2=Taguchi |first2=Fumihiro |title=Incorporation of Spike and Membrane Glycoproteins into Coronavirus Virions |journal=Viruses |date=3 April 2015 |volume=7 |issue=4 |pages=1700–1725 |pmid=25855243 |pmc=4411675 |doi=10.3390/v7041700 |doi-access=free}}

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. This cleavage may occur upon receptor binding, or the spike protein may be pre-cleaved such as by Furin at a furin cleavage site if one is present.

Like other class I fusion proteins, the spike protein undergoes a very large conformational change during the fusion process. Both the pre-fusion and post-fusion states of several coronaviruses, especially SARS-CoV-2, have been studied by cryo-electron microscopy.{{cite journal |last1=Walls |first1=Alexandra C. |last2=Park |first2=Young-Jun |last3=Tortorici |first3=M. Alejandra |last4=Wall |first4=Abigail |last5=McGuire |first5=Andrew T. |last6=Veesler |first6=David |title=Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein |journal=Cell |date=April 2020 |volume=181 |issue=2 |pages=281–292.e6 |doi=10.1016/j.cell.2020.02.058 |pmid=32155444 |pmc=7102599 }}{{cite journal |last1=Klein |first1=Steffen |last2=Cortese |first2=Mirko |last3=Winter |first3=Sophie L. |last4=Wachsmuth-Melm |first4=Moritz |last5=Neufeldt |first5=Christopher J. |last6=Cerikan |first6=Berati |last7=Stanifer |first7=Megan L. |last8=Boulant |first8=Steeve |last9=Bartenschlager |first9=Ralf |last10=Chlanda |first10=Petr |title=SARS-CoV-2 structure and replication characterized by in situ cryo-electron tomography |journal=Nature Communications |date=December 2020 |volume=11 |issue=1 |pages=5885 |doi=10.1038/s41467-020-19619-7|pmid=33208793 |pmc=7676268 |bibcode=2020NatCo..11.5885K }}{{cite journal |last1=Cai |first1=Yongfei |last2=Zhang |first2=Jun |last3=Xiao |first3=Tianshu |last4=Peng |first4=Hanqin |last5=Sterling |first5=Sarah M. |last6=Walsh |first6=Richard M. |last7=Rawson |first7=Shaun |last8=Rits-Volloch |first8=Sophia |last9=Chen |first9=Bing |title=Distinct conformational states of SARS-CoV-2 spike protein |journal=Science |date=25 September 2020 |volume=369 |issue=6511 |pages=1586–1592 |doi=10.1126/science.abd4251|pmid=32694201 |pmc=7464562 |bibcode=2020Sci...369.1586C }} 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.

File:Novel Coronavirus SARS-CoV-2 (50960620707) (cropped).jpg 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).]]

{{Infobox genome

| image = File:SARS-CoV-2 genome.svg

| caption = Genomic organisation of isolate Wuhan-Hu-1, the earliest sequenced sample of SARS-CoV-2, indicating the location of the S gene

| taxId = 86693

| size = 29,903 bases

| year = 2020

| ucsc_assembly = wuhCor1

}}

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. Protein trafficking of spike proteins appears to depend on the coronavirus subgroup: when expressed in isolation without other viral proteins, spike proteins from betacoronaviruses are able to reach the cell surface, while those from alphacoronaviruses and gammacoronaviruses are retained intracellularly. In the presence of the M protein, spike protein trafficking is altered and instead is retained at the ERGIC, the site at which viral assembly occurs. In SARS-CoV-2, both the M and the E protein modulate spike protein trafficking through different mechanisms.{{cite journal |last1=Boson |first1=Bertrand |last2=Legros |first2=Vincent |last3=Zhou |first3=Bingjie |last4=Siret |first4=Eglantine |last5=Mathieu |first5=Cyrille |last6=Cosset |first6=François-Loïc |last7=Lavillette |first7=Dimitri |last8=Denolly |first8=Solène |title=The SARS-CoV-2 envelope and membrane proteins modulate maturation and retention of the spike protein, allowing assembly of virus-like particles |journal=Journal of Biological Chemistry |date=January 2021 |volume=296 |pages=100111 |doi=10.1074/jbc.RA120.016175|pmid=33229438 |pmc=7833635 |doi-access=free }}

File:Pbio.3000815.g001.PNG L.png, showing the positions of the four structural proteins and components of the extracellular environment.{{cite journal |last1=Goodsell |first1=David S. |last2=Voigt |first2=Maria |last3=Zardecki |first3=Christine |last4=Burley |first4=Stephen K. |title=Integrative illustration for coronavirus outreach |journal=PLOS Biology |date=6 August 2020 |volume=18 |issue=8 |pages=e3000815 |doi=10.1371/journal.pbio.3000815 |pmid=32760062 |pmc=7433897 |doi-access=free }}]]

The spike protein is not required for viral assembly or the formation of virus-like particles; however, presence of spike may influence the size of the envelope.{{cite journal |last1=Neuman |first1=Benjamin W. |last2=Kiss |first2=Gabriella |last3=Kunding |first3=Andreas H. |last4=Bhella |first4=David |last5=Baksh |first5=M. Fazil |last6=Connelly |first6=Stephen |last7=Droese |first7=Ben |last8=Klaus |first8=Joseph P. |last9=Makino |first9=Shinji |last10=Sawicki |first10=Stanley G. |last11=Siddell |first11=Stuart G. |last12=Stamou |first12=Dimitrios G. |last13=Wilson |first13=Ian A. |last14=Kuhn |first14=Peter |last15=Buchmeier |first15=Michael J. |title=A structural analysis of M protein in coronavirus assembly and morphology |journal=Journal of Structural Biology |date=April 2011 |volume=174 |issue=1 |pages=11–22 |doi=10.1016/j.jsb.2010.11.021|pmid=21130884 |pmc=4486061 }} 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. Examination of virions using cryo-electron microscopy suggests that there are approximately 25{{cite journal |last1=Ke |first1=Zunlong |last2=Oton |first2=Joaquin |last3=Qu |first3=Kun |last4=Cortese |first4=Mirko |last5=Zila |first5=Vojtech |last6=McKeane |first6=Lesley |last7=Nakane |first7=Takanori |last8=Zivanov |first8=Jasenko |last9=Neufeldt |first9=Christopher J. |last10=Cerikan |first10=Berati |last11=Lu |first11=John M. |last12=Peukes |first12=Julia |last13=Xiong |first13=Xiaoli |last14=Kräusslich |first14=Hans-Georg |last15=Scheres |first15=Sjors H. W. |last16=Bartenschlager |first16=Ralf |last17=Briggs |first17=John A. G. |title=Structures and distributions of SARS-CoV-2 spike proteins on intact virions |journal=Nature |date=17 December 2020 |volume=588 |issue=7838 |pages=498–502 |doi=10.1038/s41586-020-2665-2|pmid=32805734 |pmc=7116492 |bibcode=2020Natur.588..498K }} to 100 spike trimers per virion.

The spike protein is responsible for viral entry into the host cell, a required early step in viral replication. It is essential for replication. It performs this function in two steps, first binding to a receptor on the surface of the host cell through interactions with the S1 region, and then fusing the viral and cellular membranes through the action of the S2 region.{{cite journal |last1=V’kovski |first1=Philip |last2=Kratzel |first2=Annika |last3=Steiner |first3=Silvio |last4=Stalder |first4=Hanspeter |last5=Thiel |first5=Volker |title=Coronavirus biology and replication: implications for SARS-CoV-2 |journal=Nature Reviews Microbiology |date=March 2021 |volume=19 |issue=3 |pages=155–170 |doi=10.1038/s41579-020-00468-6|pmid=33116300 |pmc=7592455 }} 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 interaction of the receptor-binding domain in the S1 region with its target receptor on the cell surface initiates the process of viral entry. Different coronaviruses target different cell-surface receptors, sometimes using sugar molecules such as sialic acids, or forming protein-protein interactions with proteins exposed on the cell surface. Different coronaviruses vary widely in their target receptor, although some such as SARS-CoV-1 and HCoV-NL63 use the same receptor despite having widely divergent spike proteins (21% amino acid identity, and only 14% in the RBD).{{Cite journal |last=Lin |first=Han-Xin |last2=Feng |first2=Yan |last3=Tu |first3=Xinming |last4=Zhao |first4=Xuesen |last5=Hsieh |first5=Chih-Heng |last6=Griffin |first6=Lauren |last7=Junop |first7=Murray |last8=Zhang |first8=Chengsheng |date=September 2011 |title=Characterization of the spike protein of human coronavirus NL63 in receptor binding and pseudotype virus entry |url=https://pmc.ncbi.nlm.nih.gov/articles/PMC7114368/ |journal=Virus Research |volume=160 |issue=1-2 |pages=283–293 |doi=10.1016/j.virusres.2011.06.029 |issn=1872-7492 |pmc=7114368 |pmid=21798295}} The presence of a target receptor that S1 can bind is a determinant of host range and cell tropism.{{cite journal |last1=Lim |first1=Yvonne |last2=Ng |first2=Yan |last3=Tam |first3=James |last4=Liu |first4=Ding |title=Human Coronaviruses: A Review of Virus–Host Interactions |journal=Diseases |date=25 July 2016 |volume=4 |issue=3 |pages=26 |doi=10.3390/diseases4030026|pmid=28933406 |pmc=5456285 |doi-access=free }} Human serum albumin binds to the S1 region, competing with ACE2 and therefore restricting viral entry into cells.{{Cite journal |last1=Varricchio |first1=Romualdo |last2=De Simone |first2=Giovanna |last3=Vita |first3=Gian Marco |last4=Nocera Cariola |first4=Walter |last5=Viscardi |first5=Maurizio |last6=Brandi |first6=Sergio |last7=Picazio |first7=Gerardo |last8=Zerbato |first8=Verena |last9=Koncan |first9=Raffaella |last10=Segat |first10=Ludovica |last11=Di Bella |first11=Stefano |last12=Fusco |first12=Giovanna |last13=Ascenzi |first13=Paolo |last14=di Masi |first14=Alessandra |title=Human serum albumin binds spike protein and protects cells from SARS-CoV-2 infection by modulating the RAS pathway |journal=Aspects of Molecular Medicine |date=2024 |language=en |volume=3 |pages=100033 |doi=10.1016/j.amolm.2023.100033|doi-access=free }}

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. Coronaviruses vary in which part of the viral life cycle these cleavages occur, particularly the S1/S2 cleavage. Many coronaviruses are cleaved at S1/S2 before viral exit from the virus-producing cell, by furin and other proprotein convertases; in SARS-CoV-2 a polybasic furin cleavage site is present at this position. Others may be cleaved by extracellular proteases such as elastase, by proteases located on the cell surface after receptor binding, or by proteases found in lysosomes after endocytosis. The specific proteases responsible for this cleavage depends on the virus, cell type, and local environment. In SARS-CoV, the serine protease TMPRSS2 is important for this process, with additional contributions from cysteine proteases cathepsin B and cathepsin L in endosomes.{{cite journal | vauthors = Jackson CB, Farzan M, Chen B, Choe H | title = Mechanisms of SARS-CoV-2 entry into cells | journal = Nature Reviews Molecular Cell Biology | volume = 23 | issue=1 | pages = 3–20 | date = 2022 | doi = 10.1038/s41580-021-00418-x | pmc = 8491763 | pmid = 34611326}} Trypsin and trypsin-like proteases have also been reported to contribute. In SARS-CoV-2, TMPRSS2 is the primary protease for S2' cleavage, and its presence is reported to be essential for viral infection, with cathepsin L protease being functional, but not essential.

File:6nb6 prefusion 6m3w postfusion spike.png

Like other class I fusion proteins, the spike protein in its pre-fusion conformation is in a metastable state. A dramatic conformational change is triggered to induce the heptad repeats in the S2 region to refold into an extended six-helix bundle, causing the fusion peptide to interact with the cell membrane and bringing the viral and cell membranes into close proximity. Receptor binding and proteolytic cleavage (sometimes known as "priming") are required, but additional triggers for this conformational change vary depending on the coronavirus and local environment.{{cite journal |last1=White |first1=Judith M. |last2=Whittaker |first2=Gary R. |title=Fusion of Enveloped Viruses in Endosomes |journal=Traffic |date=June 2016 |volume=17 |issue=6 |pages=593–614 |doi=10.1111/tra.12389|pmid=26935856 |pmc=4866878 }} In vitro studies of SARS-CoV suggest a dependence on calcium concentration. Unusually for coronaviruses, infectious bronchitis virus, which infects birds, can be triggered by low pH alone; for other coronaviruses, low pH is not itself a trigger but may be required for activity of proteases, which in turn are required for fusion. The location of membrane fusion—at the plasma membrane or in endosomes—may vary based on the availability of these triggers for conformational change. Fusion of the viral and cell membranes permits the entry of the virus' positive-sense RNA genome into the host cell cytosol, after which expression of viral proteins begins.

In addition to fusion of viral and host cell membranes, some coronavirus spike proteins can initiate membrane fusion between infected cells and neighboring cells, forming syncytia.{{cite journal |last1=Belouzard |first1=Sandrine |last2=Millet |first2=Jean K. |last3=Licitra |first3=Beth N. |last4=Whittaker |first4=Gary R. |title=Mechanisms of Coronavirus Cell Entry Mediated by the Viral Spike Protein |journal=Viruses |date=20 June 2012 |volume=4 |issue=6 |pages=1011–1033 |doi=10.3390/v4061011|pmid=22816037 |pmc=3397359 |doi-access=free }} This behavior can be observed in infected cells in cell culture.{{cite journal |last1=Buchrieser |first1=Julian |last2=Dufloo |first2=Jérémy |last3=Hubert |first3=Mathieu |last4=Monel |first4=Blandine |last5=Planas |first5=Delphine |last6=Rajah |first6=Maaran Michael |last7=Planchais |first7=Cyril |last8=Porrot |first8=Françoise |last9=Guivel-Benhassine |first9=Florence |last10=Van der Werf |first10=Sylvie |last11=Casartelli |first11=Nicoletta |last12=Mouquet |first12=Hugo |last13=Bruel |first13=Timothée |last14=Schwartz |first14=Olivier |title=Syncytia formation by SARS-CoV-2-infected cells |journal=The EMBO Journal |date=December 2020 |volume=39 |issue=23 |pages=e106267 |doi=10.15252/embj.2020106267|pmid=33051876 |pmc=7646020 }} Syncytia have been observed in patient tissue samples from infections with SARS-CoV, MERS-CoV, and SARS-CoV-2, though some reports highlight a difference in syncytia formation between the SARS-CoV and SARS-CoV-2 spikes attributed to sequence differences near the S1/S2 cleavage site.{{cite journal |last1=Zhang |first1=Zhengrong |last2=Zheng |first2=You |last3=Niu |first3=Zubiao |last4=Zhang |first4=Bo |last5=Wang |first5=Chenxi |last6=Yao |first6=Xiaohong |last7=Peng |first7=Haoran |last8=Franca |first8=Del Nonno |last9=Wang |first9=Yunyun |last10=Zhu |first10=Yichao |last11=Su |first11=Yan |last12=Tang |first12=Meng |last13=Jiang |first13=Xiaoyi |last14=Ren |first14=He |last15=He |first15=Meifang |last16=Wang |first16=Yuqi |last17=Gao |first17=Lihua |last18=Zhao |first18=Ping |last19=Shi |first19=Hanping |last20=Chen |first20=Zhaolie |last21=Wang |first21=Xiaoning |last22=Piacentini |first22=Mauro |last23=Bian |first23=Xiuwu |last24=Melino |first24=Gerry |last25=Liu |first25=Liang |last26=Huang |first26=Hongyan |last27=Sun |first27=Qiang |title=SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination |journal=Cell Death & Differentiation |date=20 April 2021 |volume=28 |issue=9 |pages=2765–2777 |doi=10.1038/s41418-021-00782-3|pmid=33879858 |pmc=8056997 }}{{cite journal |last1=Braga |first1=Luca |last2=Ali |first2=Hashim |last3=Secco |first3=Ilaria |last4=Chiavacci |first4=Elena |last5=Neves |first5=Guilherme |last6=Goldhill |first6=Daniel |last7=Penn |first7=Rebecca |last8=Jimenez-Guardeño |first8=Jose M. |last9=Ortega-Prieto |first9=Ana M. |last10=Bussani |first10=Rossana |last11=Cannatà |first11=Antonio |last12=Rizzari |first12=Giorgia |last13=Collesi |first13=Chiara |last14=Schneider |first14=Edoardo |last15=Arosio |first15=Daniele |last16=Shah |first16=Ajay M. |last17=Barclay |first17=Wendy S. |last18=Malim |first18=Michael H. |last19=Burrone |first19=Juan |last20=Giacca |first20=Mauro |title=Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia |journal=Nature |date=3 June 2021 |volume=594 |issue=7861 |pages=88–93 |doi=10.1038/s41586-021-03491-6|pmid=33827113 |pmc=7611055 |bibcode=2021Natur.594...88B |doi-access=free }}{{cite journal |last1=Lin |first1=Liangyu |last2=Li |first2=Qing |last3=Wang |first3=Ying |last4=Shi |first4=Yufang |title=Syncytia formation during SARS-CoV-2 lung infection: a disastrous unity to eliminate lymphocytes |journal=Cell Death & Differentiation |date=June 2021 |volume=28 |issue=6 |pages=2019–2021 |doi=10.1038/s41418-021-00795-y|pmid=33981020 |pmc=8114657 }}

Because it is exposed on the surface of the virus, the spike protein is a major antigen to which neutralizing antibodies are developed.{{Cite journal |last=Ho |first=Mitchell |date=April 2020 |title=Perspectives on the development of neutralizing antibodies against SARS-CoV-2 |journal=Antibody Therapeutics |volume=3 |issue=2 |pages=109–114 |doi=10.1093/abt/tbaa009 |issn=2516-4236 |pmc=7291920 |pmid=32566896}}{{Cite journal |last1=Yang |first1=Lifei |last2=Liu |first2=Weihan |last3=Yu |first3=Xin |last4=Wu |first4=Meng |last5=Reichert |first5=Janice M. |last6=Ho |first6=Mitchell |date=July 2020 |title=COVID-19 antibody therapeutics tracker: a global online database of antibody therapeutics for the prevention and treatment of COVID-19 |journal=Antibody Therapeutics |volume=3 |issue=3 |pages=205–212 |doi=10.1093/abt/tbaa020 |issn=2516-4236 |pmc=7454247 |pmid=33215063}} Its extensive glycosylation can serve as a glycan shield that hides epitopes from the immune system. Due to the outbreak of SARS and the COVID-19 pandemic, antibodies to SARS-CoV and SARS-CoV-2 spike proteins have been extensively studied. Antibodies to the SARS-CoV and SARS-CoV-2 spike proteins have been identified that target epitopes on the receptor-binding domain{{cite journal |last1=Premkumar |first1=Lakshmanane |last2=Segovia-Chumbez |first2=Bruno |last3=Jadi |first3=Ramesh |last4=Martinez |first4=David R. |last5=Raut |first5=Rajendra |last6=Markmann |first6=Alena |last7=Cornaby |first7=Caleb |last8=Bartelt |first8=Luther |last9=Weiss |first9=Susan |last10=Park |first10=Yara |last11=Edwards |first11=Caitlin E. |last12=Weimer |first12=Eric |last13=Scherer |first13=Erin M. |last14=Rouphael |first14=Nadine |last15=Edupuganti |first15=Srilatha |last16=Weiskopf |first16=Daniela |last17=Tse |first17=Longping V. |last18=Hou |first18=Yixuan J. |last19=Margolis |first19=David |last20=Sette |first20=Alessandro |last21=Collins |first21=Matthew H. |last22=Schmitz |first22=John |last23=Baric |first23=Ralph S. |last24=de Silva |first24=Aravinda M. |title=The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients |journal=Science Immunology |date=11 June 2020 |volume=5 |issue=48 |pages=eabc8413 |doi=10.1126/sciimmunol.abc8413|pmid=32527802 |pmc=7292505 }} or interfere with the process of conformational change. The majority of antibodies from infected individuals target the receptor-binding domain.{{cite journal |last1=Harvey |first1=William T. |last2=Carabelli |first2=Alessandro M. |last3=Jackson |first3=Ben |last4=Gupta |first4=Ravindra K. |last5=Thomson |first5=Emma C. |last6=Harrison |first6=Ewan M. |last7=Ludden |first7=Catherine |last8=Reeve |first8=Richard |last9=Rambaut |first9=Andrew |last10=Peacock |first10=Sharon J. |last11=Robertson |first11=David L. |title=SARS-CoV-2 variants, spike mutations and immune escape |journal=Nature Reviews Microbiology |date=July 2021 |volume=19 |issue=7 |pages=409–424 |doi=10.1038/s41579-021-00573-0|pmid=34075212 |pmc=8167834 }}{{Cite journal |last1=Hong |first1=Jessica |last2=Kwon |first2=Hyung Joon |last3=Cachau |first3=Raul |last4=Chen |first4=Catherine Z. |last5=Butay |first5=Kevin John |last6=Duan |first6=Zhijian |last7=Li |first7=Dan |last8=Ren |first8=Hua |last9=Liang |first9=Tianyuzhou |last10=Zhu |first10=Jianghai |last11=Dandey |first11=Venkata P. |last12=Martin |first12=Negin P. |last13=Esposito |first13=Dominic |last14=Ortega-Rodriguez |first14=Uriel |last15=Xu |first15=Miao |date=2022-05-03 |title=Dromedary camel nanobodies broadly neutralize SARS-CoV-2 variants |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=119 |issue=18 |pages=e2201433119 |doi=10.1073/pnas.2201433119 |doi-access=free |issn=1091-6490 |pmc=9170159 |pmid=35476528|bibcode=2022PNAS..11901433H }} More recently antibodies targeting the S2 subunit of the spike protein have been reported with broad neutralization activities against variants.{{Cite journal |last1=Buffington |first1=Jesse |last2=Duan |first2=Zhijian |last3=Kwon |first3=Hyung Joon |last4=Hong |first4=Jessica |last5=Li |first5=Dan |last6=Feng |first6=Mingqian |last7=Xie |first7=Hang |last8=Ho |first8=Mitchell |date=June 2023 |title=Identification of nurse shark VNAR single-domain antibodies targeting the spike S2 subunit of SARS-CoV-2 |journal=FASEB Journal|volume=37 |issue=6 |pages=e22973 |doi=10.1096/fj.202202099RR |issn=1530-6860 |pmid=37191949|s2cid=258717083 |doi-access=free |pmc=10715488 }}

{{Main|COVID-19 vaccine}}

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.{{cite journal |last1=Flanagan |first1=Katie L. |last2=Best |first2=Emma |last3=Crawford |first3=Nigel W. |last4=Giles |first4=Michelle |last5=Koirala |first5=Archana |last6=Macartney |first6=Kristine |last7=Russell |first7=Fiona |last8=Teh |first8=Benjamin W. |last9=Wen |first9=Sophie CH |title=Progress and Pitfalls in the Quest for Effective SARS-CoV-2 (COVID-19) Vaccines |journal=Frontiers in Immunology |date=2 October 2020 |volume=11 |pages=579250 |doi=10.3389/fimmu.2020.579250|pmid=33123165 |pmc=7566192 |hdl=11343/251733 |hdl-access=free |doi-access=free }}{{cite journal |last1=Le |first1=Tung Thanh |last2=Cramer |first2=Jakob P. |last3=Chen |first3=Robert |last4=Mayhew |first4=Stephen |title=Evolution of the COVID-19 vaccine development landscape |journal=Nature Reviews Drug Discovery |date=October 2020 |volume=19 |issue=10 |pages=667–668 |doi=10.1038/d41573-020-00151-8|pmid=32887942 |s2cid=221503034 |doi-access=free }}{{cite journal |last1=Kyriakidis |first1=Nikolaos C. |last2=López-Cortés |first2=Andrés |last3=González |first3=Eduardo Vásconez |last4=Grimaldos |first4=Alejandra Barreto |last5=Prado |first5=Esteban Ortiz |title=SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates |journal=npj Vaccines |date=December 2021 |volume=6 |issue=1 |pages=28 |doi=10.1038/s41541-021-00292-w|pmid=33619260 |pmc=7900244 }} 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.{{cite journal |last1=Fauci |first1=Anthony S. |title=The story behind COVID-19 vaccines |journal=Science |date=9 April 2021 |volume=372 |issue=6538 |pages=109 |doi=10.1126/science.abi8397|pmid=33833099 |bibcode=2021Sci...372..109F |s2cid=233186026 |doi-access= }}{{cite journal |last1=Koenig |first1=Paul-Albert |last2=Schmidt |first2=Florian I. |title=Spike D614G — A Candidate Vaccine Antigen Against Covid-19 |journal=New England Journal of Medicine |date=17 June 2021 |volume=384 |issue=24 |pages=2349–2351 |doi=10.1056/NEJMcibr2106054|pmid=34133867 |doi-access=free }}

According to a study published in January 2023, markedly elevated levels of full-length spike protein unbound by antibodies were found in people who developed postvaccine myocarditis (vs. controls that remained healthy). However, these results do not alter the risk-benefit ratio favoring vaccination against COVID-19 to prevent severe clinical outcomes.{{cite journal |title=Circulating Spike Protein Detected in Post–COVID-19 mRNA Vaccine Myocarditis |doi=10.1161/CIRCULATIONAHA.122.061025 |date=4 January 2023 |journal=Circulation |quote=Extensive antibody profiling and T-cell responses in the individuals who developed postvaccine myocarditis were essentially indistinguishable from those of vaccinated control subjects, [...] A notable finding was that markedly elevated levels of full-length spike protein (33.9±22.4 pg/mL), unbound by antibodies, were detected in the plasma of individuals with postvaccine myocarditis, [...] (unpaired t test; P<0.0001).|last1=Yonker |first1=Lael M. |last2=Swank |first2=Zoe |last3=Bartsch |first3=Yannic C. |last4=Burns |first4=Madeleine D. |last5=Kane |first5=Abigail |last6=Boribong |first6=Brittany P. |last7=Davis |first7=Jameson P. |last8=Loiselle |first8=Maggie |last9=Novak |first9=Tanya |last10=Senussi |first10=Yasmeen |last11=Cheng |first11=Chi-An |last12=Burgess |first12=Eleanor |last13=Edlow |first13=Andrea G. |last14=Chou |first14=Janet |last15=Dionne |first15=Audrey |last16=Balaguru |first16=Duraisamy |last17=Lahoud-Rahme |first17=Manuella |last18=Arditi |first18=Moshe |last19=Julg |first19=Boris |last20=Randolph |first20=Adrienne G. |last21=Alter |first21=Galit |author21-link=Galit Alter |last22=Fasano |first22=Alessio |last23=Walt |first23=David R. |volume=147 |issue=11 |pages=867–876 |pmid=36597886 |pmc=10010667 |s2cid=255475007 }}{{Primary source inline|reason=WP:MEDRS|date=January 2023}}

File:REGN-COV2 binding SARS-CoV-2 spike protein.png (blue) and imdevimab (orange) interacting with the receptor-binding domain of the spike protein (pink).{{cite journal |last1=Wrapp |first1=Daniel |last2=Wang |first2=Nianshuang |last3=Corbett |first3=Kizzmekia S. |last4=Goldsmith |first4=Jory A. |last5=Hsieh |first5=Ching-Lin |last6=Abiona |first6=Olubukola |last7=Graham |first7=Barney S. |last8=McLellan |first8=Jason S. |title=Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation |journal=Science |date=13 March 2020 |volume=367 |issue=6483 |pages=1260–1263 |pmid=32075877 |pmc=7164637 |doi=10.1126/science.abb2507 |bibcode=2020Sci...367.1260W }}{{cite journal |last1=Hansen |first1=Johanna |last2=Baum |first2=Alina |last3=Pascal |first3=Kristen E. |last4=Russo |first4=Vincenzo |last5=Giordano |first5=Stephanie |last6=Wloga |first6=Elzbieta |last7=Fulton |first7=Benjamin O. |last8=Yan |first8=Ying |last9=Koon |first9=Katrina |last10=Patel |first10=Krunal |last11=Chung |first11=Kyung Min |last12=Hermann |first12=Aynur |last13=Ullman |first13=Erica |last14=Cruz |first14=Jonathan |last15=Rafique |first15=Ashique |last16=Huang |first16=Tammy |last17=Fairhurst |first17=Jeanette |last18=Libertiny |first18=Christen |last19=Malbec |first19=Marine |last20=Lee |first20=Wen-yi |last21=Welsh |first21=Richard |last22=Farr |first22=Glen |last23=Pennington |first23=Seth |last24=Deshpande |first24=Dipali |last25=Cheng |first25=Jemmie |last26=Watty |first26=Anke |last27=Bouffard |first27=Pascal |last28=Babb |first28=Robert |last29=Levenkova |first29=Natasha |last30=Chen |first30=Calvin |last31=Zhang |first31=Bojie |last32=Romero Hernandez |first32=Annabel |last33=Saotome |first33=Kei |last34=Zhou |first34=Yi |last35=Franklin |first35=Matthew |last36=Sivapalasingam |first36=Sumathi |last37=Lye |first37=David Chien |last38=Weston |first38=Stuart |last39=Logue |first39=James |last40=Haupt |first40=Robert |last41=Frieman |first41=Matthew |last42=Chen |first42=Gang |last43=Olson |first43=William |last44=Murphy |first44=Andrew J. |last45=Stahl |first45=Neil |last46=Yancopoulos |first46=George D. |last47=Kyratsous |first47=Christos A. |title=Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail |journal=Science |date=21 August 2020 |volume=369 |issue=6506 |pages=1010–1014 |doi=10.1126/science.abd0827|pmid=32540901 |pmc=7299284 |bibcode=2020Sci...369.1010H }}]]

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:{{cite web |title=Therapeutic Management of Nonhospitalized Adults With COVID-19 |website=Covid-19 Treatment Guidelines |url=https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/nonhospitalized-adults--therapeutic-management/https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/nonhospitalized-adults--therapeutic-management/ |publisher=National Institutes of Health |access-date=11 August 2021 |archive-date=4 December 2021 |archive-url=https://web.archive.org/web/20211204215843/https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/nonhospitalized-adults--therapeutic-management/https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/nonhospitalized-adults--therapeutic-management/ |url-status=dead }} bamlanivimab/etesevimab,{{cite web |url=https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=11331 |title=etesevimab |website=IUPHAR/BPS Guide to Pharmacology|accessdate=2021-02-10}}{{cite press release|title=Lilly announces agreement with U.S. government to supply 300,000 vials of investigational neutralizing antibody bamlanivimab (LY-CoV555) in an effort to fight COVID-19 |url=https://investor.lilly.com/news-releases/news-release-details/lilly-announces-agreement-us-government-supply-300000-vials|website=Eli Lilly and Company|date=October 28, 2020 }} casirivimab/imdevimab,{{cite web | title=Casirivimab injection, solution, concentrate Imdevimab injection, solution, concentrate REGEN-COV- casirivimab and imdevimab kit | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f5bf7a31-7e17-4a94-805c-d231ea458fb0 | access-date=18 March 2021}} and sotrovimab.{{cite web | title=Sotrovimab injection, solution, concentrate | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aa5cca2e-4351-4f81-b0e5-3303ac0b2474 | access-date=15 June 2021}} 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.

{{Main|Variants of SARS-CoV-2}}

Throughout the COVID-19 pandemic, the genome of SARS-CoV-2 viruses was sequenced many times, resulting in identification of thousands of distinct variants.{{cite journal |last1=Koyama |first1=Takahiko |last2=Platt |first2=Daniel |last3=Parida |first3=Laxmi |title=Variant analysis of SARS-CoV-2 genomes |journal=Bulletin of the World Health Organization |date=1 July 2020 |volume=98 |issue=7 |pages=495–504 |doi=10.2471/BLT.20.253591|pmid=32742035 |pmc=7375210 }} 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). The evolution rate in the spike gene is higher than that observed in the genome overall.{{cite journal |last1=Winger |first1=Anna |last2=Caspari |first2=Thomas |title=The Spike of Concern—The Novel Variants of SARS-CoV-2 |journal=Viruses |date=27 May 2021 |volume=13 |issue=6 |pages=1002 |doi=10.3390/v13061002|pmid=34071984 |pmc=8229995 |doi-access=free }} 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{{cite journal |last1=Saputri |first1=Dianita S. |last2=Li |first2=Songling |last3=van Eerden |first3=Floris J. |last4=Rozewicki |first4=John |last5=Xu |first5=Zichang |last6=Ismanto |first6=Hendra S. |last7=Davila |first7=Ana |last8=Teraguchi |first8=Shunsuke |last9=Katoh |first9=Kazutaka |last10=Standley |first10=Daron M. |title=Flexible, Functional, and Familiar: Characteristics of SARS-CoV-2 Spike Protein Evolution |journal=Frontiers in Microbiology |date=17 September 2020 |volume=11 |pages=2112 |doi=10.3389/fmicb.2020.02112|pmid=33042039 |pmc=7527407 |doi-access=free }} and are undergoing positive selection.{{cite journal |last1=Cagliani |first1=Rachele |last2=Forni |first2=Diego |last3=Clerici |first3=Mario |last4=Sironi |first4=Manuela |title=Computational Inference of Selection Underlying the Evolution of the Novel Coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 |journal=Journal of Virology |date=June 2020 |volume=94 |issue=12 |pages=e00411-20 |doi=10.1128/JVI.00411-20|pmid=32238584 |pmc=7307108 }}

Spike protein mutations raise concern because they may affect infectivity or transmissibility, or facilitate immune escape. The mutation D614G has arisen independently in multiple viral lineages and become dominant among sequenced genomes;{{cite journal |last1=Isabel |first1=Sandra |last2=Graña-Miraglia |first2=Lucía |last3=Gutierrez |first3=Jahir M. |last4=Bundalovic-Torma |first4=Cedoljub |last5=Groves |first5=Helen E. |last6=Isabel |first6=Marc R. |last7=Eshaghi |first7=AliReza |last8=Patel |first8=Samir N. |last9=Gubbay |first9=Jonathan B. |last10=Poutanen |first10=Tomi |last11=Guttman |first11=David S. |last12=Poutanen |first12=Susan M. |title=Evolutionary and structural analyses of SARS-CoV-2 D614G spike protein mutation now documented worldwide |journal=Scientific Reports |date=December 2020 |volume=10 |issue=1 |pages=14031 |doi=10.1038/s41598-020-70827-z|pmid=32820179 |pmc=7441380 |bibcode=2020NatSR..1014031I }}{{cite journal |last1=Korber |first1=Bette |last2=Fischer |first2=Will M. |last3=Gnanakaran |first3=Sandrasegaram |last4=Yoon |first4=Hyejin |last5=Theiler |first5=James |last6=Abfalterer |first6=Werner |last7=Hengartner |first7=Nick |last8=Giorgi |first8=Elena E. |last9=Bhattacharya |first9=Tanmoy |last10=Foley |first10=Brian |last11=Hastie |first11=Kathryn M. |last12=Parker |first12=Matthew D. |last13=Partridge |first13=David G. |last14=Evans |first14=Cariad M. |last15=Freeman |first15=Timothy M. |last16=de Silva |first16=Thushan I. |last17=McDanal |first17=Charlene |last18=Perez |first18=Lautaro G. |last19=Tang |first19=Haili |last20=Moon-Walker |first20=Alex |last21=Whelan |first21=Sean P. |last22=LaBranche |first22=Celia C. |last23=Saphire |first23=Erica O. |last24=Montefiori |first24=David C. |last25=Angyal |first25=Adrienne |last26=Brown |first26=Rebecca L. |last27=Carrilero |first27=Laura |last28=Green |first28=Luke R. |last29=Groves |first29=Danielle C. |last30=Johnson |first30=Katie J. |last31=Keeley |first31=Alexander J. |last32=Lindsey |first32=Benjamin B. |last33=Parsons |first33=Paul J. |last34=Raza |first34=Mohammad |last35=Rowland-Jones |first35=Sarah |last36=Smith |first36=Nikki |last37=Tucker |first37=Rachel M. |last38=Wang |first38=Dennis |last39=Wyles |first39=Matthew D. |title=Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus |journal=Cell |date=August 2020 |volume=182 |issue=4 |pages=812–827.e19 |pmid=32697968 |pmc=7332439 |doi=10.1016/j.cell.2020.06.043}} it may have advantages in infectivity and transmissibility possibly due to increasing the density of spikes on the viral surface,{{cite journal |last1=Zhang |first1=Lizhou |last2=Jackson |first2=Cody B. |last3=Mou |first3=Huihui |last4=Ojha |first4=Amrita |last5=Peng |first5=Haiyong |last6=Quinlan |first6=Brian D. |last7=Rangarajan |first7=Erumbi S. |last8=Pan |first8=Andi |last9=Vanderheiden |first9=Abigail |last10=Suthar |first10=Mehul S. |last11=Li |first11=Wenhui |last12=Izard |first12=Tina |last13=Rader |first13=Christoph |last14=Farzan |first14=Michael |last15=Choe |first15=Hyeryun |title=SARS-CoV-2 spike-protein D614G mutation increases virion spike density and infectivity |journal=Nature Communications |date=December 2020 |volume=11 |issue=1 |pages=6013 |doi=10.1038/s41467-020-19808-4|pmid=33243994 |pmc=7693302 |bibcode=2020NatCo..11.6013Z }} increasing the proportion of binding-competent conformations or improving stability,{{cite journal |last1=Jackson |first1=Cody B. |last2=Zhang |first2=Lizhou |last3=Farzan |first3=Michael |last4=Choe |first4=Hyeryun |title=Functional importance of the D614G mutation in the SARS-CoV-2 spike protein |journal=Biochemical and Biophysical Research Communications |date=January 2021 |volume=538 |pages=108–115 |pmid=33220921 |pmc=7664360 |doi=10.1016/j.bbrc.2020.11.026}} but it does not affect vaccines.{{cite journal |last1=McAuley |first1=Alexander J. |title=Experimental and in silico evidence suggests vaccines are unlikely to be affected by D614G mutation in SARS-CoV-2 spike protein |journal=npj Vaccines |date=October 2020 |volume=5 |pages=96 |doi=10.1038/s41541-020-00246-8|pmid=33083031 |pmc=7546614 }} 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,{{cite journal |last1=Liu |first1=Yang |title=The N501Y Spike substitution enhances SARS-CoV-2 infection and transmission |journal=Nature |date=November 2021 |volume=602 |issue=7896 |pages=294–299 |doi=10.1038/s41586-021-04245-0 |pmid=34818667 |pmc=8900207 |s2cid=244647259 }} reduced vaccine efficacy,{{cite journal |last1=Abdool Karim |first1=S.S. |title=New SARS-CoV-2 variants — clinical, public health, and vaccine implications |journal=New England Journal of Medicine |date=2021 |volume=384 |issue=19 |pages=1866–1868 |pmid=33761203 |pmc=8008749 |doi=10.1056/NEJMc2100362}} and the ability of SARS-CoV-2 to infect new rodent species.{{cite journal |last1=Kuiper |first1=Michael |title=But Mouse, you are not alone: On some severe acute respiratory syndrome coronavirus 2 variants infecting mice |journal=ILAR Journal |date=2021 |volume=62 |issue=1–2 |pages=48–59 |doi=10.1093/ilar/ilab031 |pmid=35022734 |pmc=9236659 }} N501Y increases the affinity of spike for human ACE2 by around 10-fold,{{Cite journal |last1=Barton |first1=Michael I |last2=MacGowan |first2=Stuart A |last3=Kutuzov |first3=Mikhail A |last4=Dushek |first4=Omer |last5=Barton |first5=Geoffrey John |last6=van der Merwe |first6=P Anton |date=2021-08-26 |editor-last=Fouchier |editor-first=Ron AM |editor2-last=Van der Meer |editor2-first=Jos W |editor3-last=Fouchier |editor3-first=Ron AM |title=Effects of common mutations in the SARS-CoV-2 Spike RBD and its ligand, the human ACE2 receptor on binding affinity and kinetics |journal=eLife |volume=10 |pages=e70658 |doi=10.7554/eLife.70658 |doi-access=free |issn=2050-084X |pmc=8480977 |pmid=34435953}} which could underlie some of fitness advantages conferred by this mutation even though the relationship between affinity and infectivity is complex.{{Cite journal |last1=MacGowan |first1=Stuart A. |last2=Barton |first2=Michael I. |last3=Kutuzov |first3=Mikhail |last4=Dushek |first4=Omer |last5=Merwe |first5=P. Anton van der |last6=Barton |first6=Geoffrey J. |date=2022-03-02 |title=Missense variants in human ACE2 strongly affect binding to SARS-CoV-2 Spike providing a mechanism for ACE2 mediated genetic risk in Covid-19: A case study in affinity predictions of interface variants |journal=PLOS Computational Biology |language=en |volume=18 |issue=3 |pages=e1009922 |doi=10.1371/journal.pcbi.1009922 |issn=1553-7358 |pmc=8920257 |pmid=35235558 |bibcode=2022PLSCB..18E9922M |doi-access=free }} 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.{{cite journal |last1=Callaway |first1=Ewen |title=The mutation that helps Delta spread like wildfire |journal=Nature |date=2021 |volume=596 |issue=7873 |pages=472–473 |doi=10.1038/d41586-021-02275-2 |pmid=34417582 |bibcode=2021Natur.596..472C |s2cid=237254466 }}{{cite journal |last1=Peacock |first1=T.P. |title=The SARS-CoV-2 variants associated with infections in India, B.1.617, show enhanced Spike cleavage by furin |journal=bioRxiv |date=2021 |doi=10.1101/2021.05.28.446163 |s2cid=235249387 |url=https://eprints.whiterose.ac.uk/198940/1/The%20SARS-CoV-2%20variants%20associated%20with%20infections%20in%20India%2C%20B.1.617%2C%20show%20enhanced%20spike%20cleavage%20by%20furin.pdf}} Mutations at position E484, particularly E484K, have been associated with immune escape and reduced antibody binding.

The SARS-CoV-2 Omicron variant is notable for having an unusually high number of mutations in the spike protein.{{Cite web|date=26 November 2021|title=Classification of Omicron (B.1.1.529): SARS-CoV-2 Variant of Concern|url=https://www.who.int/news/item/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern|url-status=live|access-date=26 November 2021|website=World Health Organization|archive-date=26 November 2021|archive-url=https://web.archive.org/web/20211126180836/https://www.who.int/news/item/26-11-2021-classification-of-omicron-%28b.1.1.529%29-sars-cov-2-variant-of-concern}} 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{{Cite journal |vauthors=Brown KA, Gubbay J, Hopkins J, Patel S, Buchan SA, Daneman N, Goneau LW |date=2021-05-25 |title=S-Gene Target Failure as a Marker of Variant B.1.1.7 Among SARS-CoV-2 Isolates in the Greater Toronto Area, December 2020 to March 2021 |url=https://doi.org/10.1001/jama.2021.5607 |journal=JAMA |volume=325 |issue=20 |pages=2115–2116 |doi=10.1001/jama.2021.5607 |pmid=33830171 |pmc=8033504 |issn=0098-7484}}{{cite tech report |title=Methods for the detection and identification of SARS-CoV-2 variants |publisher=European Centre for Disease Prevention and Control/World Health Organization Regional Office for Europe |date=3 March 2021 |location=Stockholm and Copenhagen |url=https://www.ecdc.europa.eu/en/publications-data/methods-detection-and-identification-sars-cov-2-variants |at=Diagnostic screening assays of known VOCs}} and the Omicron variant.{{cite tech report |type=Briefing |title=SARS-CoV-2 variants of concern and variants under investigation in England Variant of concern: Omicron, VOC21NOV-01 (B.1.1.529), technical briefing 30 |id=GOV-10547 |institution=Public Health England |date=3 December 2021 |url=https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1038404/Technical_Briefing_30.pdf |format=PDF |access-date=15 December 2021 |archive-date=11 December 2021 |archive-url=https://web.archive.org/web/20211211164628/https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1038404/Technical_Briefing_30.pdf |url-status=live }}

In 2021, Circulation Research and Salk had a new study that proves COVID-19 can be also a vascular disease, not only respiratory disease. The scientists created an “pseudovirus”, surrounded by SARS-CoV-2 spike proteins but without any actual virus. And pseudovirus resulted in damaging lungs and arteries of animal models. It shows SARS-CoV-2 spike protein alone can cause vascular disease and could explain some covid-19 patients who suffered from strokes, or other vascular problems in other parts of human body at the same time. The team replicated the process by removing replicating capabilities of virus and showed the same damaging effect on vascular cells again.{{cite web | url=https://www.salk.edu/news-release/the-novel-coronavirus-spike-protein-plays-additional-key-role-in-illness/|title=The novel coronavirus' spike protein plays additional key role in illness|publisher=Salk researchers|date=2021-04-30|archive-date=2022-12-01|archive-url=https://web.archive.org/web/20221201074109/https://www.salk.edu/news-release/the-novel-coronavirus-spike-protein-plays-additional-key-role-in-illness/}}{{cite journal |title=SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2|publisher=AHA Journals|date=2021-03-31|doi=10.1161/CIRCRESAHA.121.318902 |last1=Lei |first1=Yuyang |last2=Zhang |first2=Jiao |last3=Schiavon |first3=Cara R. |last4=He |first4=Ming |last5=Chen |first5=Lili |last6=Shen |first6=Hui |last7=Zhang |first7=Yichi |last8=Yin |first8=Qian |last9=Cho |first9=Yoshitake |last10=Andrade |first10=Leonardo |last11=Shadel |first11=Gerald S. |last12=Hepokoski |first12=Mark |last13=Lei |first13=Ting |last14=Wang |first14=Hongliang |last15=Zhang |first15=Jin |last16=Yuan |first16=Jason X.-J. |last17=Malhotra |first17=Atul |last18=Manor |first18=Uri |last19=Wang |first19=Shengpeng |last20=Yuan |first20=Zu-Yi |last21=Shyy |first21=John Y-J. |journal=Circulation Research |volume=128 |issue=9 |pages=1323–1326 |pmid=33784827 |pmc=8091897 |s2cid=232430540 }}

{{further|COVID-19 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.{{cite web |type=Fact check |title=COVID-19 vaccines are not 'cytotoxic' |publisher=Reuters |date=18 June 2021 |url=https://www.reuters.com/article/factcheck-vaccine-cytotoxic-idUSL2N2O01XP}}{{cite web |title=The 'deadly' coronavirus spike protein (according to antivaxxers) |author=Gorski DH |publisher=Science-Based Medicine |date=24 May 2021 |url=https://sciencebasedmedicine.org/the-deadly-coronavirus-spike-protein/}} 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.{{Cite web | vauthors = McCarthy B | date = 5 May 2021 |title=Debunking the anti-vaccine hoax about 'vaccine shedding'|url=https://www.politifact.com/article/2021/may/06/debunking-anti-vaccine-hoax-about-vaccine-shedding/|access-date=11 May 2021|website=PolitiFact}}{{Cite web | vauthors = Fiore K |date=29 April 2021|title=The Latest Anti-Vax Myth: 'Vaccine Shedding'|url=https://www.medpagetoday.com/special-reports/exclusives/92336|access-date=11 May 2021|website=MedPage Today}}

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.{{cite journal |last1=Vance |first1=Tyler D.R. |last2=Lee |first2=Jeffrey E. |title=Virus and eukaryote fusogen superfamilies |journal=Current Biology |date=July 2020 |volume=30 |issue=13 |pages=R750–R754 |doi=10.1016/j.cub.2020.05.029|pmid=32634411 |pmc=7336913 |bibcode=2020CBio...30.R750V }} The S2 region of the spike protein responsible for membrane fusion is more highly conserved than the S1 region responsible for receptor interactions. The S1 region appears to have undergone significant diversifying selection.{{cite journal |last1=Li |first1=F. |title=Evidence for a Common Evolutionary Origin of Coronavirus Spike Protein Receptor-Binding Subunits |journal=Journal of Virology |date=1 March 2012 |volume=86 |issue=5 |pages=2856–2858 |doi=10.1128/jvi.06882-11|pmid=22205743 |pmc=3302248 }}

Within the S1 region, the N-terminal domain (NTD) is more conserved than the C-terminal domain (CTD). The NTD's galectin-like protein fold suggests a relationship with structurally similar cellular proteins from which it may have evolved through gene capture from the host. It has been suggested that the CTD may have evolved from the NTD by gene duplication. The surface-exposed position of the CTD, vulnerable to the host immune system, may place this region under high selective pressure. Comparisons of the structures of different coronavirus CTDs suggests they may be under diversifying selection{{cite journal |last1=Shang |first1=Jian |last2=Zheng |first2=Yuan |last3=Yang |first3=Yang |last4=Liu |first4=Chang |last5=Geng |first5=Qibin |last6=Luo |first6=Chuming |last7=Zhang |first7=Wei |last8=Li |first8=Fang |title=Cryo-EM structure of infectious bronchitis coronavirus spike protein reveals structural and functional evolution of coronavirus spike proteins |journal=PLOS Pathogens |date=23 April 2018 |volume=14 |issue=4 |pages=e1007009 |doi=10.1371/journal.ppat.1007009|pmid=29684066 |pmc=5933801 |doi-access=free }} and in some cases, distantly related coronaviruses that use the same cell-surface receptor may do so through convergent evolution.

{{reflist}}

• {{cite news |last1=Scudellari |first1=Megan |title=How the coronavirus infects cells — and why Delta is so dangerous |url=https://www.nature.com/articles/d41586-021-02039-y |access-date=15 August 2021 |work=Nature |date=28 July 2021}}
• {{cite web |last1=Iwasa |first1=Janet |last2=Meyer |first2=Miriah |last3=Lex |first3=Alexander |last4=Rogers |first4=Jen |last5=Liu |first5=Ann (Hui) |last6=Riggi |first6=Margot |title=Building a visual consensus model of the SARS-CoV-2 life cycle |url=https://animationlab.utah.edu/cova |website=Animation Lab |publisher=University of Utah |access-date=15 August 2021}}

{{Coronavirus genomes}}

{{Viral proteins}}

Category:Coronavirus proteins

Category:Viral protein class

Category:Viral structural proteins