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Receptor binding, immune escape, and protein stability direct the natural selection of SARS-CoV-2 variants.
J Biol Chem. 2021 10; 297(4):101208.JB

Abstract

Emergence of new severe acute respiratory syndrome coronavirus 2 variants has raised concerns related to the effectiveness of vaccines and antibody therapeutics developed against the unmutated wildtype virus. Here, we examined the effect of the 12 most commonly occurring mutations in the receptor-binding domain of the spike protein on its expression, stability, activity, and antibody escape potential. Stability was measured using thermal denaturation, and the activity and antibody escape potential were measured using isothermal titration calorimetry in terms of binding to the human angiotensin-converting enzyme 2 and to neutralizing human antibody CC12.1, respectively. Our results show that mutants differ in their expression levels. Of the eight best-expressed mutants, two (N501Y and K417T/E484K/N501Y) showed stronger affinity to angiotensin-converting enzyme 2 compared with the wildtype, whereas four (Y453F, S477N, T478I, and S494P) had similar affinity and two (K417N and E484K) had weaker affinity than the wildtype. Compared with the wildtype, four mutants (K417N, Y453F, N501Y, and K417T/E484K/N501Y) had weaker affinity for the CC12.1 antibody, whereas two (S477N and S494P) had similar affinity, and two (T478I and E484K) had stronger affinity than the wildtype. Mutants also differ in their thermal stability, with the two least stable mutants showing reduced expression. Taken together, these results indicate that multiple factors contribute toward the natural selection of variants, and all these factors need to be considered to understand the evolution of the virus. In addition, since not all variants can escape a given neutralizing antibody, antibodies to treat new variants can be chosen based on the specific mutations in that variant.

Authors+Show Affiliations

Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. Electronic address: krishna.mallela@cuanschutz.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34543625

Citation

Upadhyay, Vaibhav, et al. "Receptor Binding, Immune Escape, and Protein Stability Direct the Natural Selection of SARS-CoV-2 Variants." The Journal of Biological Chemistry, vol. 297, no. 4, 2021, p. 101208.
Upadhyay V, Lucas A, Panja S, et al. Receptor binding, immune escape, and protein stability direct the natural selection of SARS-CoV-2 variants. J Biol Chem. 2021;297(4):101208.
Upadhyay, V., Lucas, A., Panja, S., Miyauchi, R., & Mallela, K. M. G. (2021). Receptor binding, immune escape, and protein stability direct the natural selection of SARS-CoV-2 variants. The Journal of Biological Chemistry, 297(4), 101208. https://doi.org/10.1016/j.jbc.2021.101208
Upadhyay V, et al. Receptor Binding, Immune Escape, and Protein Stability Direct the Natural Selection of SARS-CoV-2 Variants. J Biol Chem. 2021;297(4):101208. PubMed PMID: 34543625.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Receptor binding, immune escape, and protein stability direct the natural selection of SARS-CoV-2 variants. AU - Upadhyay,Vaibhav, AU - Lucas,Alexandra, AU - Panja,Sudipta, AU - Miyauchi,Ryuki, AU - Mallela,Krishna M G, Y1 - 2021/09/17/ PY - 2021/08/01/received PY - 2021/09/14/revised PY - 2021/09/15/accepted PY - 2021/9/21/pubmed PY - 2021/11/11/medline PY - 2021/9/20/entrez KW - ACE2 KW - COVID-19 KW - SARS-CoV-2 KW - antibodies KW - protein binding KW - protein expression KW - protein function KW - protein stability KW - protein structure KW - variants SP - 101208 EP - 101208 JF - The Journal of biological chemistry JO - J Biol Chem VL - 297 IS - 4 N2 - Emergence of new severe acute respiratory syndrome coronavirus 2 variants has raised concerns related to the effectiveness of vaccines and antibody therapeutics developed against the unmutated wildtype virus. Here, we examined the effect of the 12 most commonly occurring mutations in the receptor-binding domain of the spike protein on its expression, stability, activity, and antibody escape potential. Stability was measured using thermal denaturation, and the activity and antibody escape potential were measured using isothermal titration calorimetry in terms of binding to the human angiotensin-converting enzyme 2 and to neutralizing human antibody CC12.1, respectively. Our results show that mutants differ in their expression levels. Of the eight best-expressed mutants, two (N501Y and K417T/E484K/N501Y) showed stronger affinity to angiotensin-converting enzyme 2 compared with the wildtype, whereas four (Y453F, S477N, T478I, and S494P) had similar affinity and two (K417N and E484K) had weaker affinity than the wildtype. Compared with the wildtype, four mutants (K417N, Y453F, N501Y, and K417T/E484K/N501Y) had weaker affinity for the CC12.1 antibody, whereas two (S477N and S494P) had similar affinity, and two (T478I and E484K) had stronger affinity than the wildtype. Mutants also differ in their thermal stability, with the two least stable mutants showing reduced expression. Taken together, these results indicate that multiple factors contribute toward the natural selection of variants, and all these factors need to be considered to understand the evolution of the virus. In addition, since not all variants can escape a given neutralizing antibody, antibodies to treat new variants can be chosen based on the specific mutations in that variant. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/34543625/Receptor_binding_immune_escape_and_protein_stability_direct_the_natural_selection_of_SARS_CoV_2_variants_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(21)01010-3 DB - PRIME DP - Unbound Medicine ER -