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<StructureSection load='7qus' size='350' side='right' caption='C3 symmetry of SARS-CoV-2 spike protein' scene=''> | <StructureSection load='7qus' size='350' side='right' caption='C3 symmetry of SARS-CoV-2 spike protein' scene=''> | ||
==SARS-CoV-2 Spike Protein== | ==SARS-CoV-2 Spike Protein== | ||
| - | The SARS-CoV-2 spike protein (Severe acute respiratory syndrome coronavirus 2) is a protein that has emerged from the COVID-19 virus beginning in December 2019. It has had a significant global impact on human health.<ref>Weisblum, Y.; Schmidt, F.; Zhang, F.; DaSilva, J.; Poston, D.; Lorenzi, J. C. C.; Muecksch, F.; Rutkowska, M.; Hoffmann, H.-H.; Michailidis, E.; Gaebler, C.; Agudelo, M.; Cho, A.; Wang, Z.; Gazumyan, A.; Cipolla, M.; Luchsinger, L.; Hillyer, C. D.; Caskey, M.; Robbiani, D. F.; Rice, C. M.; Nussenzweig, M. C.; Hatziioannou, T.; Bieniasz, P. D. Escape from Neutralizing Antibodies by SARS-COV-2 Spike Protein Variants. eLife '''2020''', 9.</ref> The spike protein is a major immunogenic target for virus neutralization and is the current focus of many vaccine development efforts.<ref>Henderson, R.; Edwards, R. J.; Mansouri, K.; Janowska, K.; Stalls, V.; Gobeil, S.; Kopp, M.; Hsu, A.; Borgnia, M.; Parks, R.; Haynes, B. F.; Acharya, P. Controlling the SARS-COV-2 Spike Glycoprotein Conformation | + | The SARS-CoV-2 spike protein (Severe acute respiratory syndrome coronavirus 2) is a protein that has emerged from the COVID-19 virus beginning in December 2019. It has had a significant global impact on human health.<ref>Weisblum, Y.; Schmidt, F.; Zhang, F.; DaSilva, J.; Poston, D.; Lorenzi, J. C. C.; Muecksch, F.; Rutkowska, M.; Hoffmann, H.-H.; Michailidis, E.; Gaebler, C.; Agudelo, M.; Cho, A.; Wang, Z.; Gazumyan, A.; Cipolla, M.; Luchsinger, L.; Hillyer, C. D.; Caskey, M.; Robbiani, D. F.; Rice, C. M.; Nussenzweig, M. C.; Hatziioannou, T.; Bieniasz, P. D. Escape from Neutralizing Antibodies by SARS-COV-2 Spike Protein Variants. eLife '''2020''', 9.</ref> The spike protein is a major immunogenic target for virus neutralization and is the current focus of many vaccine development efforts.<ref>Henderson, R.; Edwards, R. J.; Mansouri, K.; Janowska, K.; Stalls, V.; Gobeil, S.; Kopp, M.; Hsu, A.; Borgnia, M.; Parks, R.; Haynes, B. F.; Acharya, P. Controlling the SARS-COV-2 Spike Glycoprotein Conformation '''2020'''.</ref> The virus is still present as of 2022. Most people infected with the disease experience an array of symptoms including fever, headaches, fatigue, sore throat, cough, etc. The spike protein is on the surface of the SARS-CoV-2 virus which then initiate infection in host cells.<ref name="bangaru">Bangaru, S.; Ozorowski, G.; Turner, H. L.; Antanasijevic, A.; Huang, D.; Wang, X.; Torres, J. L.; Diedrich, J. K.; Tian, J.-H.; Portnoff, A. D.; Patel, N.; Massare, M. J.; Yates, J. R.; Nemazee, D.; Paulson, J. C.; Glenn, G.; Smith, G.; Ward, A. B. Structural Analysis of Full-Length SARS-COV-2 Spike Protein from an Advanced Vaccine Candidate. Science '''2020''', 370 (6520), 1089–1094.</ref> |
== Function == | == Function == | ||
The SARS-CoV-2 spike protein helps extract antibodies that neutralize viruses into the body. To enter a cell and start an infection, the spike protein in SARS-CoV-2 (SARS-2-S) interacts with the human <scene name='91/919045/Ace2_sars-cov-2_spike_protein/1'>ACE2</scene> receptor. The ACE2 (Angiotensin-converting enzyme 2) is an enzyme that can be found in the membrane of cells in the following: intestines, kidney, testis, gallbladder, and heart.<ref>Xia, X. Domains and Functions of Spike Protein in SARS-COV-2 in the Context of Vaccine Design. Viruses '''2021''', 13(1).</ref> The spike (S) protein has the following: S1 and S2 subunits, extracellular N-terminus, a transmembrane domain that is being anchored into the viral membrane, and a short intracellular C-terminal. In the native state– the protein is folded to be able to operate and function properly. In this case the SARS-CoV-2 spike protein begins to exist as an inactive precursor when in this specific state. However, in a viral infection state, the target cell's proteases will activate the S-protein which is being cleaved into both the S1 and S2 subunits. As a result, this allows for the activation of the membrane fusion after the result of viral entry are in the targeted cells.<ref name="huang">Huang, Y.; Yang, C.; Xu, X.-feng; Xu, W.; Liu, S.-wen. Structural and Functional Properties of SARS-COV-2 Spike Protein: Potential Antivirus Drug Development for Covid-19. Acta Pharmacologica Sinica '''2020''', 41 (9), 1141–1149.</ref> The S typically exists in a metastable– where it will have no small disturbances, prefusion conformation.<ref name="bangaru">Bangaru, S.; Ozorowski, G.; Turner, H. L.; Antanasijevic, A.; Huang, D.; Wang, X.; Torres, J. L.; Diedrich, J. K.; Tian, J.-H.; Portnoff, A. D.; Patel, N.; Massare, M. J.; Yates, J. R.; Nemazee, D.; Paulson, J. C.; Glenn, G.; Smith, G.; Ward, A. B. Structural Analysis of Full-Length SARS-COV-2 Spike Protein from an Advanced Vaccine Candidate. Science '''2020''', 370 (6520), 1089–1094.</ref> | The SARS-CoV-2 spike protein helps extract antibodies that neutralize viruses into the body. To enter a cell and start an infection, the spike protein in SARS-CoV-2 (SARS-2-S) interacts with the human <scene name='91/919045/Ace2_sars-cov-2_spike_protein/1'>ACE2</scene> receptor. The ACE2 (Angiotensin-converting enzyme 2) is an enzyme that can be found in the membrane of cells in the following: intestines, kidney, testis, gallbladder, and heart.<ref>Xia, X. Domains and Functions of Spike Protein in SARS-COV-2 in the Context of Vaccine Design. Viruses '''2021''', 13(1).</ref> The spike (S) protein has the following: S1 and S2 subunits, extracellular N-terminus, a transmembrane domain that is being anchored into the viral membrane, and a short intracellular C-terminal. In the native state– the protein is folded to be able to operate and function properly. In this case the SARS-CoV-2 spike protein begins to exist as an inactive precursor when in this specific state. However, in a viral infection state, the target cell's proteases will activate the S-protein which is being cleaved into both the S1 and S2 subunits. As a result, this allows for the activation of the membrane fusion after the result of viral entry are in the targeted cells.<ref name="huang">Huang, Y.; Yang, C.; Xu, X.-feng; Xu, W.; Liu, S.-wen. Structural and Functional Properties of SARS-COV-2 Spike Protein: Potential Antivirus Drug Development for Covid-19. Acta Pharmacologica Sinica '''2020''', 41 (9), 1141–1149.</ref> The S typically exists in a metastable– where it will have no small disturbances, prefusion conformation.<ref name="bangaru">Bangaru, S.; Ozorowski, G.; Turner, H. L.; Antanasijevic, A.; Huang, D.; Wang, X.; Torres, J. L.; Diedrich, J. K.; Tian, J.-H.; Portnoff, A. D.; Patel, N.; Massare, M. J.; Yates, J. R.; Nemazee, D.; Paulson, J. C.; Glenn, G.; Smith, G.; Ward, A. B. Structural Analysis of Full-Length SARS-COV-2 Spike Protein from an Advanced Vaccine Candidate. Science '''2020''', 370 (6520), 1089–1094.</ref> | ||
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<scene name='91/919045/Nc_sars-cov-2_spike_protein/2'>N-terminus (blue) to C-terminus (red)</scene> | <scene name='91/919045/Nc_sars-cov-2_spike_protein/2'>N-terminus (blue) to C-terminus (red)</scene> | ||
== Mutations == | == Mutations == | ||
| - | The viral DNA experiences numerous spike protein changes to enable it to infect a new mammalian host and leap species. The <scene name='91/919045/D614g_sars-cov-2_spike_protein/1'>D614G mutation</scene> is a common mutation in SARS-CoV-2 spike protein. It has no effect on the affinity of monomeric spike protein for ACE2 and residue 614 is found outside the receptor binding domain (RBD). The mutation dramatically increases the virus's capacity to infect and spread. <ref>Jackson, C. B.; Zhang, L.; Farzan, M.; Choe, H. Functional Importance of the D614G Mutation in the SARS-COV-2 Spike Protein. Biochemical and Biophysical Research Communications 2021, 538, 108–115.</ref> Drugs created to target protein-protein interactions, such as vaccines, may be affected by mutations found at the interface between the ACE2 receptor and the spike protein. | + | The viral DNA experiences numerous spike protein changes to enable it to infect a new mammalian host and leap species. The <scene name='91/919045/D614g_sars-cov-2_spike_protein/1'>D614G mutation</scene> is a common mutation in SARS-CoV-2 spike protein. It has no effect on the affinity of monomeric spike protein for ACE2 and residue 614 is found outside the receptor binding domain (RBD). The mutation dramatically increases the virus's capacity to infect and spread. <ref>Jackson, C. B.; Zhang, L.; Farzan, M.; Choe, H. Functional Importance of the D614G Mutation in the SARS-COV-2 Spike Protein. Biochemical and Biophysical Research Communications '''2021''', 538, 108–115.</ref> Drugs created to target protein-protein interactions, such as vaccines, may be affected by mutations found at the interface between the ACE2 receptor and the spike protein. |
<ref>Guruprasad, L. Human Sars-CoV‐2 Spike Protein Mutations. Proteins: Structure, Function, and Bioinformatics '''2021''', 89 (5), 569–576.</ref> | <ref>Guruprasad, L. Human Sars-CoV‐2 Spike Protein Mutations. Proteins: Structure, Function, and Bioinformatics '''2021''', 89 (5), 569–576.</ref> | ||
== Structural Highlights == | == Structural Highlights == | ||
| - | The SARS-CoV-2 spike protein has a primary, secondary, tertiary, and quaternary structure. The motif present in the SARS-CoV-2 spike protein is the beta sandwich– where there are 1273 amino acids. Beta sandwiches are characterized by having two opposed <scene name='91/919045/Sheet_sars-cov-2_spike_protein/3'>beta sheets</scene>. Both the <scene name='91/919045/S1_sars-cov-2_spike_protein/1'>S1</scene> and <scene name='91/919045/S2_sars-cov-2_spike_protein/1'>S2</scene> subunits are the last two regions that manage the processes of the receptor binding and the membrane fusing. <ref>Berger, I.; Schaffitzel, C. The Sars-COV-2 Spike Protein: Balancing Stability and Infectivity. Cell Research 2020, 30 (12), 1059–1060.</ref> In the S1 subunit, it is composed of an N-terminal, receptor-binding domain, and the fusion of peptides. Heptapeptide 1 and 2, TM domain, and cytoplasmic domain fusion are the reason for viral fusion and entry. In the S2 subunit, the S-protein trimers have a shape of a crown-like looking halo that is on the surrounding area of the viral particle. Because of the structure of the coronavirus S protein monomers this causes both the S1 and S2 subunits to be formulated into a “bulbous head and stalk region”. The 3-D form of the protein plays a role in receptor recognition cell membrane fusion process. The Angiotensin-converting enzyme 2 is recognized and bound by the receptor-binding domain of the S1 subunit. Through the two-heptad repeat domain, the S2 subunit facilitates viral cell membrane fusion, resulting in a six <scene name='91/919045/Helix_sars-cov-2_spike_protein/4'>helical</scene> bundle. <ref name="huang">Huang, Y.; Yang, C.; Xu, X.-feng; Xu, W.; Liu, S.-wen. Structural and Functional Properties of SARS-COV-2 Spike Protein: Potential Antivirus Drug Development for Covid-19. Acta Pharmacologica Sinica '''2020''', 41 (9), 1141–1149.</ref> | + | The SARS-CoV-2 spike protein has a primary, secondary, tertiary, and quaternary structure. The motif present in the SARS-CoV-2 spike protein is the beta sandwich– where there are 1273 amino acids. Beta sandwiches are characterized by having two opposed <scene name='91/919045/Sheet_sars-cov-2_spike_protein/3'>beta sheets</scene>. Both the <scene name='91/919045/S1_sars-cov-2_spike_protein/1'>S1</scene> and <scene name='91/919045/S2_sars-cov-2_spike_protein/1'>S2</scene> subunits are the last two regions that manage the processes of the receptor binding and the membrane fusing. <ref>Berger, I.; Schaffitzel, C. The Sars-COV-2 Spike Protein: Balancing Stability and Infectivity. Cell Research '''2020''', 30 (12), 1059–1060.</ref> In the S1 subunit, it is composed of an N-terminal, receptor-binding domain, and the fusion of peptides. Heptapeptide 1 and 2, TM domain, and cytoplasmic domain fusion are the reason for viral fusion and entry. In the S2 subunit, the S-protein trimers have a shape of a crown-like looking halo that is on the surrounding area of the viral particle. Because of the structure of the coronavirus S protein monomers this causes both the S1 and S2 subunits to be formulated into a “bulbous head and stalk region”. The 3-D form of the protein plays a role in receptor recognition cell membrane fusion process. The Angiotensin-converting enzyme 2 is recognized and bound by the receptor-binding domain of the S1 subunit. Through the two-heptad repeat domain, the S2 subunit facilitates viral cell membrane fusion, resulting in a six <scene name='91/919045/Helix_sars-cov-2_spike_protein/4'>helical</scene> bundle. <ref name="huang">Huang, Y.; Yang, C.; Xu, X.-feng; Xu, W.; Liu, S.-wen. Structural and Functional Properties of SARS-COV-2 Spike Protein: Potential Antivirus Drug Development for Covid-19. Acta Pharmacologica Sinica '''2020''', 41 (9), 1141–1149.</ref> |
The quaternary structures are both <scene name='91/919045/Dimer/1'>dimers</scene> and <scene name='91/919045/Trimer/1'>trimers</scene> and the symmetry is asymmetric C3.<ref>Zhou, T.; Tsybovsky, Y.; Gorman, J.; Rapp, M.; Cerutti, G.; Chuang, G.-Y.; Katsamba, P. S.; Sampson, J. M.; Schön, A.; Bimela, J.; Boyington, J. C.; Nazzari, A.; Olia, A. S.; Shi, W.; Sastry, M.; Stephens, T.; Stuckey, J.; Teng, I.-T.; Wang, P.; Wang, S.; Zhang, B.; Friesner, R. A.; Ho, D. D.; Mascola, J. R.; Shapiro, L.; Kwong, P. D. Cryo-EM Structures of SARS-COV-2 Spike without and with Ace2 Reveal a Ph-Dependent Switch to Mediate Endosomal Positioning of Receptor-Binding Domains. Cell Host & Microbe '''2020''', 28 (6).</ref> | The quaternary structures are both <scene name='91/919045/Dimer/1'>dimers</scene> and <scene name='91/919045/Trimer/1'>trimers</scene> and the symmetry is asymmetric C3.<ref>Zhou, T.; Tsybovsky, Y.; Gorman, J.; Rapp, M.; Cerutti, G.; Chuang, G.-Y.; Katsamba, P. S.; Sampson, J. M.; Schön, A.; Bimela, J.; Boyington, J. C.; Nazzari, A.; Olia, A. S.; Shi, W.; Sastry, M.; Stephens, T.; Stuckey, J.; Teng, I.-T.; Wang, P.; Wang, S.; Zhang, B.; Friesner, R. A.; Ho, D. D.; Mascola, J. R.; Shapiro, L.; Kwong, P. D. Cryo-EM Structures of SARS-COV-2 Spike without and with Ace2 Reveal a Ph-Dependent Switch to Mediate Endosomal Positioning of Receptor-Binding Domains. Cell Host & Microbe '''2020''', 28 (6).</ref> | ||
Current revision
Structure
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References
- ↑ Weisblum, Y.; Schmidt, F.; Zhang, F.; DaSilva, J.; Poston, D.; Lorenzi, J. C. C.; Muecksch, F.; Rutkowska, M.; Hoffmann, H.-H.; Michailidis, E.; Gaebler, C.; Agudelo, M.; Cho, A.; Wang, Z.; Gazumyan, A.; Cipolla, M.; Luchsinger, L.; Hillyer, C. D.; Caskey, M.; Robbiani, D. F.; Rice, C. M.; Nussenzweig, M. C.; Hatziioannou, T.; Bieniasz, P. D. Escape from Neutralizing Antibodies by SARS-COV-2 Spike Protein Variants. eLife 2020, 9.
- ↑ Henderson, R.; Edwards, R. J.; Mansouri, K.; Janowska, K.; Stalls, V.; Gobeil, S.; Kopp, M.; Hsu, A.; Borgnia, M.; Parks, R.; Haynes, B. F.; Acharya, P. Controlling the SARS-COV-2 Spike Glycoprotein Conformation 2020.
- ↑ 3.0 3.1 Bangaru, S.; Ozorowski, G.; Turner, H. L.; Antanasijevic, A.; Huang, D.; Wang, X.; Torres, J. L.; Diedrich, J. K.; Tian, J.-H.; Portnoff, A. D.; Patel, N.; Massare, M. J.; Yates, J. R.; Nemazee, D.; Paulson, J. C.; Glenn, G.; Smith, G.; Ward, A. B. Structural Analysis of Full-Length SARS-COV-2 Spike Protein from an Advanced Vaccine Candidate. Science 2020, 370 (6520), 1089–1094.
- ↑ Xia, X. Domains and Functions of Spike Protein in SARS-COV-2 in the Context of Vaccine Design. Viruses 2021, 13(1).
- ↑ 5.0 5.1 Huang, Y.; Yang, C.; Xu, X.-feng; Xu, W.; Liu, S.-wen. Structural and Functional Properties of SARS-COV-2 Spike Protein: Potential Antivirus Drug Development for Covid-19. Acta Pharmacologica Sinica 2020, 41 (9), 1141–1149.
- ↑ Suzuki, Y. J.; Gychka, S. G. SARS-COV-2 Spike Protein Elicits Cell Signaling in Human Host Cells: Implications for Possible Consequences of Covid-19 Vaccines. Vaccines 2021, 9 (1), 36.
- ↑ Jackson, C. B.; Zhang, L.; Farzan, M.; Choe, H. Functional Importance of the D614G Mutation in the SARS-COV-2 Spike Protein. Biochemical and Biophysical Research Communications 2021, 538, 108–115.
- ↑ Guruprasad, L. Human Sars-CoV‐2 Spike Protein Mutations. Proteins: Structure, Function, and Bioinformatics 2021, 89 (5), 569–576.
- ↑ Berger, I.; Schaffitzel, C. The Sars-COV-2 Spike Protein: Balancing Stability and Infectivity. Cell Research 2020, 30 (12), 1059–1060.
- ↑ Zhou, T.; Tsybovsky, Y.; Gorman, J.; Rapp, M.; Cerutti, G.; Chuang, G.-Y.; Katsamba, P. S.; Sampson, J. M.; Schön, A.; Bimela, J.; Boyington, J. C.; Nazzari, A.; Olia, A. S.; Shi, W.; Sastry, M.; Stephens, T.; Stuckey, J.; Teng, I.-T.; Wang, P.; Wang, S.; Zhang, B.; Friesner, R. A.; Ho, D. D.; Mascola, J. R.; Shapiro, L.; Kwong, P. D. Cryo-EM Structures of SARS-COV-2 Spike without and with Ace2 Reveal a Ph-Dependent Switch to Mediate Endosomal Positioning of Receptor-Binding Domains. Cell Host & Microbe 2020, 28 (6).
