Coronavirus spike protein

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Coronavirus spike glycoprotein
Illustration of a SARS-CoV-2 virion
Model of the external structure of the SARS-CoV-2 virion.[1]
● Blue: envelope
● Turquoise: spike glycoprotein (S)
● Red: envelope proteins (E)
● Green: membrane proteins (M)
● Orange: glycan
Identifiers
SymbolCoV_S1
PfamPF01600
InterProIPR002551
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Spike (S) glycoprotein (sometimes also called spike protein,

solar corona",[6] gives the virus family its main name.[2]

The function of the spike

cell tropism (which cells or tissues it can infect within an organism).[4][5][7][8]

Spike glycoprotein is highly

Neutralizing antibodies target epitopes on the receptor-binding domain.[9] Most COVID-19 vaccine development efforts in response to the COVID-19 pandemic aim to activate the immune system against the spike protein.[10][11][12]

Structure

Cryo-electron microscopy structure of a SARS-CoV-2 spike protein trimer in the pre-fusion conformation, with a single monomer highlighted. The S1 NTD is shown in blue and the S1 CTD (which serves as the receptor-binding domain) is shown in pink. Helices show in orange and cyan form parts of S2 that will undergo conformational changes during fusion. The black bar at the bottom indicates the position of the viral membrane. From PDB: 6VSB​.[13]

The spike protein is very large, often 1200 to 1400

N-terminal ectodomain exposed on the virus exterior.[5][7]

Spike glycoprotein forms

protein-protein interactions that hold the trimer in place.[7]

S1

Betacoronavirus spike glycoprotein S1, receptor binding
Identifiers
SymbolbCoV_S1_RBD
PfamPF09408
InterProIPR018548
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
Betacoronavirus-like spike glycoprotein S1, N-terminal
Identifiers
SymbolbCoV_S1_N
PfamPF16451
InterProIPR032500
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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

N-acetylneuraminic acid by the NTD[15] 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.[16]

The CTD is responsible for the interactions of

SARS-CoV[7] and SARS-CoV-2[5] 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.[5][7] There are subtle differences, mainly in the RBM, between the SARS-CoV and SARS-CoV-2 spike proteins' interactions with ACE2.[5] 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.[7]

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.[4][5][7] Within the S1 region, the NTD is more highly conserved than the CTD.[7]

S2

Coronavirus spike glycoprotein S2
Identifiers
SymbolCoV_S2
PfamPF01601
InterProIPR002552
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

The S2 region of spike glycoprotein is responsible for

C-terminal tail located in the interior of the virion.[5]

Relative to S1, the S2 region is very well

conserved among coronaviruses.[5][7]

Post-translational modifications

Spike protein illustrated with and without glycosylation.[17][18]

Spike glycoprotein is heavily

palmitoylated.[5][20]

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.[4][5][7][8]

Conformational change

Like other

sterically inaccessible, while the open states have one or two S1 RBDs more accessible for receptor binding, in an open or "up" conformation.[5]

Transmission electron micrograph 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

Genomic information
Genomic organisation of isolate Wuhan-Hu-1, the earliest sequenced sample of SARS-CoV-2, indicating the location of the S gene
NCBI genome ID86693
Genome size29,903 bases
Year of completion2020
Genome browser (UCSC)

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.[20] In SARS-CoV-2, both the M and the E protein modulate spike protein trafficking through different mechanisms.[24]

respiratory mucosa, showing the positions of the four structural proteins and components of the extracellular environment.[25]

The spike protein is not required for viral assembly or the formation of

cryo-electron microscopy suggests that there are approximately 25[27] to 100 spike trimers per virion.[22][26]

Function

The spike protein is responsible for

plasma membrane and others entering from endosomes after endocytosis.[8]

Attachment

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

cell tropism.[7][9][28] Human serum albumin binds to the S1 region, competing with ACE2 and therefore restricting viral entry into cells.[29]

Human coronaviruses and their cell surface receptors
Species Genus Receptor Reference
Human coronavirus 229E Alphacoronavirus
Aminopeptidase N
 [4][30]
Human coronavirus NL63 Alphacoronavirus Angiotensin-converting enzyme 2 [4][31]
Human coronavirus HKU1 Betacoronavirus N-acetyl-9-O-acetylneuraminic acid [28][32]
Human coronavirus OC43 Betacoronavirus N-acetyl-9-O-acetylneuraminic acid [4][33]
Middle East respiratory syndrome–related coronavirus
 Betacoronavirus Dipeptidyl peptidase-4 [4][34]
Severe acute respiratory syndrome coronavirus
 Betacoronavirus Angiotensin-converting enzyme 2 [4][35]
Severe acute respiratory syndrome coronavirus 2
 Betacoronavirus
N-acetylneuraminic acid
 [5][9][36]

Proteolytic cleavage

SARS-CoV, the serine protease TMPRSS2 is important for this process, with additional contributions from cysteine proteases cathepsin B and cathepsin L in endosomes.[8][9][37] Trypsin and trypsin-like proteases have also been reported to contribute.[8] In SARS-CoV-2, TMPRSS2 is the primary protease for S2' cleavage, and its presence is reported to be essential for viral infection,[5][9] with cathepsin L protease being functional, but not essential.[37]

Membrane fusion

Comparison of the pre-fusion (orange, light blue) and post-fusion (red, dark blue) conformations of the SARS-CoV spike protein trimer. In the pre-fusion conformation, the central helix (orange) and heptad repeat 1 (HR1, light blue) are folded back on each other in an antiparallel orientation. In the post-fusion conformation, the central helix (red) and the HR1 sequence (dark blue) reorganize to form an extended trimeric coiled coil. The viral membrane is at the bottom and the host cell membrane at the top. Only key portions of the S2 subunit are shown. From PDB: 6NB6​ (pre-fusion)[38] and PDB: 6M3W​ (post-fusion).[39]

Like other

positive-sense RNA genome into the host cell cytosol, after which expression of viral proteins begins.[2][4][9]

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

MERS-CoV, and SARS-CoV-2,[42] 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.[43][44][45]

Immunogenicity

Because it is exposed on the surface of the virus, the spike protein is a major

SARS-CoV and SARS-CoV-2 spike proteins have been extensively studied.[46] Antibodies to the SARS-CoV and SARS-CoV-2 spike proteins have been identified that target epitopes on the receptor-binding domain[9][46][48] or interfere with the process of conformational change.[9] The majority of antibodies from infected individuals target the receptor-binding domain.[46][49][50] More recently antibodies targeting the S2 subunit of the spike protein have been reported with broad neutralization activities against variants.[51]

COVID-19 response

Vaccines

Main article: COVID-19 vaccine

In response to the

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.[52][53]

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.[54][non-primary source needed]

Monoclonal antibodies

imdevimab (orange) interacting with the receptor-binding domain of the spike protein (pink).[13][55]

SARS-CoV-2 variants that are less susceptible to these antibodies.[56]

SARS-CoV-2 variants

Main article: Variants of SARS-CoV-2

Throughout the

positive selection.[49][64]

Spike protein mutations raise concern because they may affect

immune escape and reduced antibody binding.[49][62]

The SARS-CoV-2 Omicron variant is notable for having an unusually high number of mutations in the spike protein.[77] 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[78][79] and the Omicron variant.[80]

Additional Key Role in Illness

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.[81][82]

Misinformation

Further information: COVID-19 misinformation

During the

cytotoxic" and mRNA vaccines containing them therefore in themselves dangerous. Spike proteins are not cytotoxic or dangerous.[83][84] Even though studies has found that spike proteins are causing amyloid-disease associated blood coagulation and fibrinolytic disturbances, along with neurologic and cardiac problems.[needs copy edit][85] 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.[86][87]

Evolution, conservation and recombination

The

diversifying selection.[89]

Within the S1 region, the N-terminal domain (NTD) is more conserved than the C-terminal domain (CTD).

selective pressure.[7] Comparisons of the structures of different coronavirus CTDs suggests they may be under diversifying selection[90] and in some cases, distantly related coronaviruses that use the same cell-surface receptor may do so through convergent evolution.[14]

References

  1. ^ Solodovnikov, Alexey; Arkhipova, Valeria (29 July 2021). "Достоверно красиво: как мы сделали 3D-модель SARS-CoV-2" [Truly beautiful: how we made the SARS-CoV-2 3D model] (in Russian). N+1. Archived from the original on 30 July 2021. Retrieved 30 July 2021.
  2. ^
    ISBN 9780128145166
    .
  3. ^
    PMID 16877062
    .
  4. ^
    PMID 32833200
    .
  5. ^
    PMID 34125455
    .
  6. PMC 7086490
    .
  7. ^
    PMID 27578435
    .
  8. ^
    PMID 29275820
    .
  9. ^
    PMID 33116300
    .
  10. ^
    PMID 33123165
    .
  11. ^
    S2CID 221503034
    .
  12. ^
    PMID 33619260
    .
  13. ^
    PMID 32075877
    .
  14. ^
    PMID 27712627
    .
  15. ^ https://doi.org/10.1126/science.abm3125
  16. ^ https://doi.org/10.1016/S0021-9258(18)63732-9
  17. ^ Zimmer, Carl (9 October 2020). "The Coronavirus Unveiled". The New York Times. Retrieved 12 August 2021.
  18. ^
    PMID 33140034
    .
  19. PMID 32363391
    .
  20. ^
    PMID 25855243
    .
  21. PMID 32155444
    .
  22. ^
    PMID 33208793
    .
  23. PMID 32694201
    .
  24. ^
    PMID 33229438
    .
  25. PMID 32760062
    .
  26. ^
    PMID 21130884
    .
  27. PMID 32805734
    .
  28. ^
    PMID 28933406
    .
  29. doi:10.1016/j.amolm.2023.100033
    .
  30. PMID 1350662
    .
  31. PMID 15897467
    .
  32. PMID 25926653
    .
  33. PMID 8317096
    .
  34. PMID 23486063
    .
  35. PMID 14647384
    .
  36. ^ https://doi.org/10.1126/science.abm3125
  37. ^
    PMID 34611326
    .
  38. PMID 30712865
    .
  39. PMID 32681106
    .
  40. ^
    PMID 26935856
    .
  41. PMID 22816037
    .
  42. ^
    PMID 33051876
    .
  43. PMID 33879858
    .
  44. PMID 33827113
    .
  45. PMID 33981020
    .
  46. ^
    PMID 32566896
    .
  47. PMID 33215063
    .
  48. PMID 32527802
    .
  49. ^
    PMID 34075212
    .
  50. PMID 35476528
    .
  51. S2CID 258717083
    .
  52. S2CID 233186026
    .
  53. PMID 34133867
    .
  54. S2CID 255475007
    . 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).
  55. PMID 32540901
    .
  56. ^ a b "Therapeutic Management of Nonhospitalized Adults With COVID-19". Covid-19 Treatment Guidelines. National Institutes of Health. Archived from the original on 4 December 2021. Retrieved 11 August 2021.
  57. ^ "etesevimab". IUPHAR/BPS Guide to Pharmacology. Retrieved 10 February 2021.
  58. ^ "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". Eli Lilly and Company (Press release). 28 October 2020.
  59. ^ "Casirivimab injection, solution, concentrate Imdevimab injection, solution, concentrate REGEN-COV- casirivimab and imdevimab kit". DailyMed. Retrieved 18 March 2021.
  60. ^ "Sotrovimab injection, solution, concentrate". DailyMed. Retrieved 15 June 2021.
  61. ^
    PMID 32742035
    .
  62. ^
    PMID 34071984
    .
  63. PMID 33042039
    .
  64. PMID 32238584
    .
  65. PMID 32820179
    .
  66. PMID 32697968
    .
  67. PMID 33243994
    .
  68. PMID 33220921
    .
  69. PMID 33083031
    .
  70. S2CID 244647259
    .
  71. PMID 33761203
    .
  72. PMID 35022734
    .
  73. PMID 34435953
    .
  74. PMID 35235558
    .
  75. S2CID 237254466
    .
  76. S2CID 235249387
    .
  77. ^ "Classification of Omicron (B.1.1.529): SARS-CoV-2 Variant of Concern". World Health Organization. 26 November 2021. Archived from the original on 26 November 2021. Retrieved 26 November 2021.
  78. PMID 33830171
    .
  79. ^ Methods for the detection and identification of SARS-CoV-2 variants (Technical report). Stockholm and Copenhagen: European Centre for Disease Prevention and Control/World Health Organization Regional Office for Europe. 3 March 2021. Diagnostic screening assays of known VOCs.
  80. ^ 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 (PDF) (Briefing). Public Health England. 3 December 2021. GOV-10547. Archived (PDF) from the original on 11 December 2021. Retrieved 15 December 2021.
  81. ^ "The novel coronavirus' spike protein plays additional key role in illness". Salk researchers. 30 April 2021. Archived from the original on 1 December 2022.
  82. S2CID 232430540
    .
  83. ^ "COVID-19 vaccines are not 'cytotoxic'" (Fact check). Reuters. 18 June 2021.
  84. ^ Gorski DH (24 May 2021). "The 'deadly' coronavirus spike protein (according to antivaxxers)". Science-Based Medicine.
  85. PMID 35579205
    .
  86. ^ McCarthy B (5 May 2021). "Debunking the anti-vaccine hoax about 'vaccine shedding'". PolitiFact. Retrieved 11 May 2021.
  87. ^ Fiore K (29 April 2021). "The Latest Anti-Vax Myth: 'Vaccine Shedding'". MedPage Today. Retrieved 11 May 2021.
  88. PMID 32634411
    .
  89. PMID 22205743
    .
  90. PMID 29684066
    .

External links
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