Shifting mutational constraints in the SARS-CoV-2 receptor-binding domain during viral evolution

• Published in: Science (American Association for the Advancement of Science) Vol. 377; no. 6604; pp. 420 - 424
• Main Authors: Starr, Tyler N., Greaney, Allison J., Hannon, William W., Loes, Andrea N., Hauser, Kevin, Dillen, Josh R., Ferri, Elena, Farrell, Ariana Ghez, Dadonaite, Bernadeta, McCallum, Matthew, Matreyek, Kenneth A., Corti, Davide, Veesler, David, Snell, Gyorgy, Bloom, Jesse D.
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 22.07.2022; American Association for the Advancement of Science
• Subjects: ACE2; Amino acids; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - metabolism; Antibodies; Binding; Biochem; Coronaviruses; COVID-19; COVID-19 - virology; Epistasis, Genetic; Evolution; Evolution, Molecular; Humans; Microbio; Mutation; Protein Binding; Proteins; Receptors; Receptors, Virus - metabolism; SARS-CoV-2 - genetics; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - metabolism; Spike protein; Viral diseases
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abo7896

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved variants with substitutions in the spike receptor-binding domain (RBD) that affect its affinity for angiotensin-converting enzyme 2 (ACE2) receptor and recognition by antibodies. These substitutions could also shape future evolution by modulating the effects of mutations at other sites—a phenomenon called epistasis. To investigate this possibility, we performed deep mutational scans to measure the effects on ACE2 binding of all single–amino acid mutations in the Wuhan-Hu-1, Alpha, Beta, Delta, and Eta variant RBDs. Some substitutions, most prominently Asn 501 →Tyr (N501Y), cause epistatic shifts in the effects of mutations at other sites. These epistatic shifts shape subsequent evolutionary change—for example, enabling many of the antibody-escape substitutions in the Omicron RBD. These epistatic shifts occur despite high conservation of the overall RBD structure. Our data shed light on RBD sequence-function relationships and facilitate interpretation of ongoing SARS-CoV-2 evolution. As proteins evolve, the mutational landscape changes because a mutation at one residue position may affect the functional consequences of a mutation at a second position. To explore how this plays out in the evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, Starr et al . measured the effects of all single-amino-acid mutations on binding of the spike protein to the cellular receptor ACE2 in the context of different SARS-CoV-2 variants (Wuhan-Hu-1, Alpha, Beta, Delta, and Eta). They show how evolution of the protein is shaping the possibility for future mutations, for example, allowing mutations that escape antibodies while maintaining binding to ACE2. —VV Deep mutational scanning reveals epistatic shifts in the effects of mutations on ACE2 binding, shaping SARS-CoV-2 evolution.