Spike Protein Structure and Assembly
The spike (S) glycoprotein is the smallest of the four major structural proteins in coronaviruses.
Explanation: This statement is incorrect. The spike (S) glycoprotein is the largest of the four major structural proteins in coronaviruses, playing a critical role in viral entry and structure.
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The S1 region of the spike glycoprotein is responsible for anchoring the protein to the viral envelope.
Explanation: This statement is incorrect. The S2 region, specifically its transmembrane helix, is responsible for anchoring the spike protein to the viral envelope.
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Coronavirus spike proteins are typically short, usually less than 500 amino acid residues.
Explanation: This statement is incorrect. Coronavirus spike proteins are generally quite large, typically ranging from 1200 to 1400 amino acid residues in length.
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A spike protein is a multi-pass transmembrane protein, passing through the host cell membrane multiple times.
Explanation: This statement is incorrect. The spike protein is a single-pass transmembrane protein, meaning it crosses the viral envelope membrane only once via a transmembrane helix, anchoring it to the viral envelope.
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Spike proteins on the virion surface assemble into heterotrimers, composed of different protein types.
Explanation: This statement is incorrect. Spike proteins assemble into homotrimers, meaning three identical protein units associate together to form the spike structure.
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The S1 subunit of the spike glycoprotein contains both the N-terminal domain (NTD) and the C-terminal domain (CTD).
Explanation: The S1 subunit of the spike glycoprotein is indeed further divided into two main domains: the N-terminal domain (NTD) and the C-terminal domain (CTD).
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The Receptor-Binding Domain (RBD) is located within the S2 subunit and mediates attachment to host cells.
Explanation: This statement is incorrect. The Receptor-Binding Domain (RBD) is located within the S1 subunit, not the S2 subunit, and it is responsible for mediating attachment to host cells.
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The C-terminal domain (CTD) of the S1 subunit is primarily involved in the membrane fusion process.
Explanation: This statement is incorrect. The C-terminal domain (CTD) of the S1 subunit is primarily involved in receptor binding, whereas the S2 subunit is responsible for mediating the membrane fusion process.
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The "fusion core" region, essential for membrane fusion, is located within the S1 subunit.
Explanation: This statement is incorrect. The "fusion core" region, which is essential for membrane fusion, is located within the S2 subunit of the spike glycoprotein.
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A single SARS-CoV-2 virion typically displays thousands of spike trimers on its surface.
Explanation: This statement is incorrect. Estimates suggest that a single SARS-CoV-2 virion typically displays approximately 25 to 100 spike trimers on its surface.
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The fusion peptide within the S2 subunit is a hydrophilic region involved in receptor binding.
Explanation: This statement is incorrect. The fusion peptide is a stretch of hydrophobic amino acids within the S2 subunit that inserts into the host cell membrane to initiate the fusion process; it is not involved in receptor binding.
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The term "peplomer" refers to the transmembrane helix region of the spike protein.
Explanation: This statement is incorrect. The term "peplomer" is used synonymously with "spike" to describe the club-shaped projections formed by the spike protein trimers on the viral surface.
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The S gene in the viral genome encodes the nucleocapsid protein, not the spike protein.
Explanation: This statement is incorrect. The S gene in the viral genome encodes the coronavirus spike protein, which is crucial for viral entry into host cells.
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What structural feature gives coronaviruses their characteristic name?
Answer: The "corona" of spikes formed by spike glycoproteins.
Explanation: The spike glycoproteins assemble into trimers that form large structures, called spikes or peplomers, projecting from the virus surface. These spikes create a distinctive appearance reminiscent of the solar corona, which is how the virus family derived its name.
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What is the approximate length range, in amino acid residues, for coronavirus spike proteins?
Explanation: Coronavirus spike proteins are substantial molecules, generally measuring between 1200 and 1400 amino acid residues. For instance, the spike protein of SARS-CoV-2 comprises 1273 residues.
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How do spike proteins assemble on the surface of a coronavirus virion?
Answer: As homotrimers of identical spike protein units.
Explanation: Spike proteins assemble into homotrimers, meaning three identical protein units associate together. These trimers then form the large spike structures that project from the viral surface.
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Viral Entry Mechanism
Coronaviruses exclusively use the ACE2 protein as their cellular receptor for entry.
Explanation: This statement is incorrect. While ACE2 is a receptor for SARS-CoV and SARS-CoV-2, coronaviruses utilize a diverse range of molecules as receptors, including other proteins like CEACAM1 and sugar molecules such as sialic acids.
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The N-terminal domain (NTD) of the S1 subunit typically binds to protein receptors in most coronaviruses.
Explanation: This statement is incorrect. In many coronaviruses, the N-terminal domain (NTD) of the S1 subunit binds to sugar molecules on the host cell surface. While some viruses use their NTD to bind protein receptors (e.g., CEACAM1), the C-terminal domain (CTD) is more commonly associated with protein receptor binding.
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The S2 region refolds into a six-helix bundle to facilitate membrane fusion after activation.
Explanation: This statement is correct. Upon activation, the heptad repeat regions (HR1 and HR2) within the S2 subunit undergo a conformational change, refolding to form a stable six-helix bundle that drives the fusion of viral and host cell membranes.
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Proteolytic cleavage, or "priming," is not necessary for the spike protein to activate its fusion machinery.
Explanation: This statement is incorrect. Proteolytic cleavage, often referred to as "priming," is essential for activating the S2 subunit's fusion machinery, enabling the virus to enter the host cell.
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The SARS-CoV-2 spike protein lacks a cleavage site recognized by the host protease furin.
Explanation: This statement is incorrect. The SARS-CoV-2 spike protein possesses a polybasic furin cleavage site at the S1/S2 boundary, which can be cleaved by the host cell protease furin.
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TMPRSS2 is a host cell protease that helps activate the SARS-CoV-2 spike protein by cleaving the S2' site.
Explanation: This statement is correct. TMPRSS2 is a host cell protease that plays a crucial role in activating the SARS-CoV-2 spike protein, particularly by cleaving at the S2' site, which is essential for viral entry.
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The spike protein remains in its stable post-fusion conformation until it encounters a host cell.
Explanation: This statement is incorrect. The spike protein exists in a metastable pre-fusion state and undergoes a dramatic conformational change upon receptor binding and proteolytic cleavage to mediate membrane fusion.
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The "open" state of the spike protein makes the receptor-binding sites inaccessible.
Explanation: This statement is incorrect. In the "open" state, one or more S1 subunits pivot outwards, exposing the receptor-binding domains for interaction with host cell receptors.
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The C-terminal domain (CTD) of the S1 subunit is responsible for binding to the ACE2 receptor in SARS-CoV-2.
Explanation: This statement is correct. The C-terminal domain (CTD) of the S1 subunit is responsible for recognizing and binding to the ACE2 receptor in both SARS-CoV and SARS-CoV-2.
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The heptad repeat regions (HR1 and HR2) in the S2 subunit are primarily involved in receptor recognition.
Explanation: This statement is incorrect. The heptad repeat regions (HR1 and HR2) in the S2 subunit are primarily involved in mediating the fusion of viral and host cell membranes after activation, not receptor recognition.
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The furin cleavage site in SARS-CoV-2 is located within the S2 subunit, away from the S1/S2 boundary.
Explanation: This statement is incorrect. The furin cleavage site in SARS-CoV-2 is located at the boundary between the S1 and S2 subunits, not within the S2 subunit itself.
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Low pH is the primary trigger for the conformational change and membrane fusion of most coronaviruses.
Explanation: This statement is incorrect. While low pH can trigger fusion for some viruses, for many coronaviruses, proteolytic cleavage events are the primary triggers for the conformational changes leading to membrane fusion.
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The S2 region is responsible for recognizing and binding to specific receptor molecules on the host cell surface.
Explanation: This statement is incorrect. The S2 region is responsible for mediating the fusion of viral and host cell membranes after the initial binding event, which is carried out by the S1 subunit.
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The spike protein being in a "metastable" state means it is structurally rigid and unchanging.
Explanation: This statement is incorrect. The "metastable" state of the spike protein refers to its pre-fusion conformation, which holds significant potential energy and is poised to undergo a large, triggered conformational change to facilitate membrane fusion.
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Which part of the spike glycoprotein is responsible for attaching to specific receptors on the host cell surface?
Answer: The Receptor-Binding Domain (RBD) within the S1 subunit
Explanation: The Receptor-Binding Domain (RBD), located within the S1 subunit, is specifically responsible for recognizing and binding to particular receptor molecules on the surface of the host cell, initiating the viral entry process.
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Which subunit of the spike glycoprotein contains the elements necessary for fusing the viral and host cell membranes?
Explanation: The S2 subunit contains the fusion peptide and the heptad repeat regions (HR1 and HR2) that undergo conformational changes to mediate the fusion of the viral and host cell membranes.
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Which domain within the S1 subunit is primarily responsible for recognizing and binding to host cell receptors like ACE2?
Answer: C-terminal domain (CTD)
Explanation: The C-terminal domain (CTD) of the S1 subunit is responsible for mediating the interaction with specific host cell receptors, such as the ACE2 receptor used by SARS-CoV and SARS-CoV-2.
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What is the function of the heptad repeat regions (HR1 and HR2) located in the S2 subunit?
Answer: Forming a six-helix bundle to mediate membrane fusion.
Explanation: The HR1 and HR2 regions within the S2 subunit are critical for membrane fusion. After activation, they refold to form a stable six-helix bundle, which drives the merging of the viral and host cell membranes.
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What critical process must occur for the S2 subunit's fusion machinery to become active?
Answer: Proteolytic cleavage at specific sites (priming)
Explanation: Proteolytic cleavage, often referred to as "priming," is essential for activating the S2 subunit's fusion machinery, enabling the virus to enter the host cell.
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What is the significance of the furin cleavage site found at the S1/S2 boundary in the SARS-CoV-2 spike protein?
Answer: It allows cleavage by furin before the virus leaves the cell, potentially enhancing infectivity.
Explanation: The polybasic furin cleavage site at the S1/S2 boundary in SARS-CoV-2 can be cleaved by the host cell protease furin before the virus exits the cell, which is thought to contribute to its infectivity and pathogenesis.
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Which host cell protease is crucial for cleaving the S2' site of the SARS-CoV-2 spike protein, facilitating entry?
Explanation: TMPRSS2 is a host cell protease that plays a crucial role in activating the SARS-CoV-2 spike protein by cleaving at the S2' site, which is considered essential for viral entry and infection.
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What does the "metastable" nature of the spike protein's pre-fusion conformation refer to?
Answer: Its potential energy state, poised for a large conformational change upon triggering.
Explanation: The "metastable" state of the spike protein refers to its pre-fusion conformation, which holds significant potential energy and is poised to undergo a large, triggered conformational change to facilitate membrane fusion.
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How does the N-terminal domain (NTD) of the S1 subunit typically function in many coronaviruses?
Answer: Binding to sugar molecules on the host cell surface.
Explanation: In many coronaviruses, the N-terminal domain (NTD) of the S1 subunit binds to sugar molecules on the host cell surface. However, some viruses utilize their NTD to bind protein receptors, such as CEACAM1.
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What is the function of the S2 region of the spike glycoprotein?
Answer: Mediating the fusion of viral and host cell membranes.
Explanation: The S2 region of the spike glycoprotein is responsible for mediating the membrane fusion between the viral envelope and the host cell membrane, a critical step that allows the virus's genetic material to enter the cell.
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Spike Protein Function and Pathogenesis
The primary role of the spike glycoprotein is to facilitate the virus's exit from an infected host cell.
Explanation: This statement is incorrect. The primary role of the spike glycoprotein is to mediate the virus's entry into a host cell, not its exit.
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The spike protein's receptor-binding specificity determines a coronavirus's host range and cell tropism.
Explanation: The specificity of the spike protein's receptor-binding domain (RBD) is indeed crucial in determining which organisms a coronavirus can infect (host range) and which specific cells or tissues within an organism it can target (cell tropism).
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The spike protein is considered poorly immunogenic because it is hidden within the viral core.
Explanation: This statement is incorrect. The spike protein is highly immunogenic precisely because it is prominently exposed on the virus's surface, making it a primary target for the host's immune system.
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The spike protein can mediate the fusion of infected cells, a phenomenon known as syncytia formation.
Explanation: This statement is correct. Some coronavirus spike proteins, including that of SARS-CoV-2, can mediate the fusion of infected cells with neighboring cells, leading to the formation of syncytia.
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The spike protein is not a target for vaccine development because it is located internally within the virus.
Explanation: This statement is incorrect. The spike protein is a primary target for vaccine development precisely because it is located on the virus's surface and is essential for entry, making it a major antigen for eliciting neutralizing antibodies.
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The SARS-CoV-2 spike protein is solely responsible for viral entry and has no proposed role in other aspects of COVID-19 illness.
Explanation: This statement is incorrect. Beyond its critical role in viral entry, recent research suggests the SARS-CoV-2 spike protein may also contribute to vascular damage, potentially explaining some vascular complications observed in COVID-19.
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A common piece of misinformation claimed that mRNA vaccines cause vaccinated individuals to shed spike proteins.
Explanation: This statement is correct. A common piece of misinformation circulating claimed that vaccinated individuals shed spike proteins, which is not biologically possible with mRNA vaccines.
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Understanding the pre-fusion conformation of the spike protein is unimportant for designing effective vaccines.
Explanation: This statement is incorrect. Understanding the pre-fusion conformation of the spike protein is crucial for comprehending the mechanism of viral entry and for designing effective vaccines and therapeutics.
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The S1 region's main function is mediating membrane fusion between the virus and the host cell.
Explanation: This statement is incorrect. The S1 region's main function is mediating the initial attachment to host cell receptors, while the S2 region is responsible for mediating membrane fusion.
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Monoclonal antibodies targeting the spike protein's RBD are used to neutralize the virus.
Explanation: This statement is correct. Monoclonal antibodies that specifically target the receptor-binding domain (RBD) of the spike protein are employed as therapeutic agents to neutralize the virus.
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The spike protein is essential for viral replication solely because it forms the structural shell of the virion.
Explanation: This statement is incorrect. While the spike protein contributes to the virion's structure, its essential role in viral replication is primarily due to its function in mediating viral entry into the host cell.
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What is the primary role of the spike (S) glycoprotein in coronaviruses?
Answer: Mediating the virus's entry into a host cell.
Explanation: The primary role of the spike glycoprotein is to mediate the virus's entry into a host cell by binding to specific receptors and fusing the viral and host cell membranes.
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Why is the spike protein considered a primary target for the host's immune system?
Answer: It is prominently exposed on the virus surface and essential for entry.
Explanation: The spike protein is highly immunogenic because it is prominently displayed on the virus's exterior and is critical for viral entry, making it a primary target for neutralizing antibodies generated by the host immune system.
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The formation of syncytia, where infected cells fuse with neighboring cells, can be mediated by which viral component?
Answer: The spike protein
Explanation: Some coronavirus spike proteins, including that of SARS-CoV-2, can mediate the fusion of infected cells with neighboring cells, leading to the formation of syncytia.
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Why are vaccines primarily designed to target the spike protein?
Answer: It is essential for viral entry and is a major surface antigen.
Explanation: The spike protein is a primary target for vaccine development because it is located on the virus's surface and is essential for entry, making it a major antigen for eliciting neutralizing antibodies.
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Beyond viral entry, what additional role has been proposed for the SARS-CoV-2 spike protein in COVID-19 illness?
Answer: Contributing to vascular damage.
Explanation: Beyond its role in viral entry, research suggests that the SARS-CoV-2 spike protein may also contribute to vascular damage, potentially explaining some vascular complications observed in COVID-19 patients.
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Which of the following is an example of misinformation regarding COVID-19 vaccines and the spike protein?
Answer: Vaccinated individuals shed spike proteins, causing harm to others.
Explanation: A common piece of misinformation claimed that vaccinated individuals shed spike proteins, which is not biologically possible with mRNA vaccines. The other statements are factual regarding vaccines and the spike protein.
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What is the function of the S1 region of the spike glycoprotein?
Answer: Interacting with host cell receptors for initial attachment.
Explanation: The S1 region of the spike glycoprotein is responsible for interacting with receptor molecules on the surface of the host cell, which constitutes the initial step in the viral entry process.
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Spike Protein Evolution and Viral Variants
The S1 region of the spike protein is more conserved across different coronaviruses than the S2 region.
Explanation: This statement is incorrect. The S2 region is significantly more conserved among coronaviruses than the S1 region because its function in membrane fusion is fundamental and less dependent on specific host cell interactions, whereas the S1 region, particularly the RBD, must adapt to different host receptors.
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Mutations in the spike protein have no significant effect on SARS-CoV-2 infectivity or immune evasion.
Explanation: This statement is incorrect. Mutations in the spike protein can significantly impact SARS-CoV-2 by potentially increasing its infectivity, transmissibility, and ability to evade the immune system (immune escape).
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The D614G mutation in the SARS-CoV-2 spike protein is associated with decreased infectivity.
Explanation: This statement is incorrect. The D614G mutation became globally dominant and is associated with increased infectivity and transmissibility of SARS-CoV-2.
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The N501Y mutation has been linked to reduced binding affinity to the human ACE2 receptor.
Explanation: This statement is incorrect. The N501Y mutation, found in variants like Alpha and Omicron, has been linked to enhanced infection, transmission, and increased binding affinity to the human ACE2 receptor.
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Mutations like E484K in the spike protein are associated with improved antibody binding.
Explanation: This statement is incorrect. Mutations like E484K are associated with immune escape, meaning they alter the protein structure to reduce the binding effectiveness of antibodies generated from prior infection or vaccination.
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S-gene target failure (SGTF) is a phenomenon used to track variants like Alpha and Omicron based on PCR test results.
Explanation: This statement is correct. S-gene target failure (SGTF), caused by a deletion in the S gene, has been utilized as a proxy marker to monitor the spread of variants such as Alpha and Omicron.
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The C-terminal domain (CTD) of the spike protein is generally more conserved than the N-terminal domain (NTD) across coronaviruses.
Explanation: This statement is incorrect. The N-terminal domain (NTD) of the S1 subunit is typically more conserved than the C-terminal domain (CTD) across coronaviruses, although the S2 subunit is the most conserved region overall.
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The S2 region is less conserved among coronaviruses because its fusion mechanism needs to adapt to diverse host receptors.
Explanation: This statement is incorrect. The S2 region is significantly *more* conserved among coronaviruses because its function in membrane fusion is fundamental and less dependent on specific host receptor interactions, unlike the S1 region.
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The term "diversifying selection" implies that mutations in the spike protein's S1 region are generally disadvantageous.
Explanation: This statement is incorrect. "Diversifying selection" implies that mutations conferring different advantages are favored in different viral populations, leading to rapid evolution and variation, often related to adapting to host immune responses or receptor interactions.
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The P681R mutation in the SARS-CoV-2 Delta variant is associated with decreased transmissibility.
Explanation: This statement is incorrect. The P681R mutation, located near the furin cleavage site, has been associated with increased infectivity and transmissibility of the SARS-CoV-2 Delta variant.
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The spike protein's RBD mutations primarily affect viral replication speed, not receptor binding or antibody recognition.
Explanation: This statement is incorrect. Mutations in the spike protein's receptor-binding domain (RBD) can significantly alter its affinity for host cell receptors and affect its recognition by antibodies, impacting infectivity, transmissibility, and immune escape.
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The higher evolution rate in the spike gene compared to the overall genome suggests it is under less selective pressure.
Explanation: This statement is incorrect. A higher evolution rate in the spike gene suggests it is under significant selective pressure, likely due to the need to adapt to host immune responses and changing receptor interactions, driving the emergence of new viral variants.
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Which region of the spike protein is generally more conserved across different coronavirus species, and why?
Answer: S2 region, due to its essential role in membrane fusion.
Explanation: The S2 subunit is significantly more conserved among coronaviruses because its function in membrane fusion is fundamental and less dependent on specific host receptor interactions, unlike the S1 region, which must adapt to different receptors.
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Which mutation in the SARS-CoV-2 spike protein became globally dominant and is linked to increased infectivity?
Explanation: The D614G mutation became globally dominant and is associated with increased infectivity and transmissibility of SARS-CoV-2, potentially by enhancing spike density or stability.
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The N501Y mutation, found in variants like Alpha and Omicron, is associated with what effect?
Answer: Enhanced binding affinity to the human ACE2 receptor.
Explanation: The N501Y mutation, present in several SARS-CoV-2 variants, has been linked to enhanced infection, transmission, and increased binding affinity to the human ACE2 receptor.
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Mutations like E484K in the spike protein contribute to which phenomenon?
Answer: Immune escape, reducing antibody effectiveness.
Explanation: Mutations such as E484K in the spike protein are associated with immune escape, which means they alter the protein structure to reduce the binding effectiveness of antibodies generated from prior infection or vaccination.
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What is S-gene target failure (SGTF), and how is it utilized?
Answer: A PCR test anomaly due to an S gene deletion, used to monitor variants like Alpha.
Explanation: S-gene target failure (SGTF) occurs when a specific deletion in the S gene prevents certain PCR tests from detecting it. This phenomenon has been used as a proxy marker to monitor the spread of variants such as Alpha and Omicron.
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What does the higher evolution rate in the spike gene imply about its role in viral adaptation?
Answer: It is under significant selective pressure for adaptation.
Explanation: A higher evolution rate in the spike gene suggests it is under significant selective pressure, likely due to the need to adapt to host immune responses and changing receptor interactions, which drives the emergence of new viral variants.
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Spike Protein Modifications and Host Interactions
N-linked glycosylation is a minor post-translational modification for the spike glycoprotein.
Explanation: This statement is incorrect. N-linked glycosylation is a major and extensive post-translational modification for the spike glycoprotein, contributing to its structure and function.
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The glycan shield on the spike protein enhances its recognition by the host immune system.
Explanation: This statement is incorrect. The "glycan shield" formed by extensive glycosylation on the spike protein can help hide antibody-binding sites (epitopes) from the host immune system, potentially hindering immune recognition.
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The similarity between the spike protein's NTD fold and cellular galectins suggests a possible evolutionary origin through gene capture.
Explanation: This statement is correct. The N-terminal domain (NTD) of the spike protein exhibits a fold similar to cellular galectins, suggesting a potential evolutionary origin through gene capture from host cellular proteins.
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The C-terminal domain (CTD) of the spike protein is thought to have evolved independently from the NTD.
Explanation: This statement is incorrect. It has been suggested that the C-terminal domain (CTD) of the spike protein may have evolved from the N-terminal domain (NTD) through a process of gene duplication.
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The M (membrane) protein and E (envelope) protein do not influence the trafficking or incorporation of the spike protein.
Explanation: This statement is incorrect. In SARS-CoV-2, both the M (membrane) protein and the E (envelope) protein modulate the trafficking of the spike protein within the host cell and influence its incorporation into new virions.
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The C-terminal tail of the spike protein anchors it to the viral envelope and interacts with the M protein.
Explanation: This statement is correct. The C-terminal tail of the spike protein is involved in anchoring it to the viral envelope and is known to interact with the M protein, facilitating its incorporation into new virions.
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Human serum albumin binding to the spike protein enhances viral entry by facilitating receptor interaction.
Explanation: This statement is incorrect. Human serum albumin can bind to the S1 region of the spike protein, potentially competing with ACE2 binding and thereby restricting viral entry into cells.
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What is the potential function of the "glycan shield" on the spike protein?
Answer: To hide antibody-binding sites (epitopes) from the immune system.
Explanation: The "glycan shield" formed by extensive glycosylation on the spike protein can help hide antibody-binding sites (epitopes) from the host immune system, potentially hindering immune recognition.
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What evolutionary relationship is suggested by the similarity between the spike protein's NTD fold and cellular galectins?
Answer: Gene capture from host cellular proteins.
Explanation: The N-terminal domain (NTD) of the spike protein exhibits a fold similar to cellular galectins, suggesting a potential evolutionary origin through gene capture from host cellular proteins.
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What is the role of the spike protein's interaction with human serum albumin?
Answer: It inhibits viral entry by competing with ACE2 binding.
Explanation: Human serum albumin can bind to the S1 region of the spike protein, potentially competing with ACE2 binding and thereby restricting viral entry into cells.
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