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Published on: June 14, 2022
Molecular Basis of Mink ACE2 Binding to SARS-CoV-2 and Its Mink-Derived Variants
Chao Su1,2, Juanhua He2,3, Pengcheng Han2,4
1Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
Abstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted between humans and minks, and some mutations in the spike (S) protein, especially in the receptor-binding domain (RBD), have been identified in mink-derived viruses. Here, we examined binding of the mink angiotensin-converting enzyme 2 (ACE2) receptor to mink-derived and important human-originating variants, and we demonstrated that most of the RBD variants increased the binding affinities to mink ACE2 (mkACE2). Cryo-electron microscopy structures of the mkACE2-RBD Y453F (with a Y-to-F change at position 453) and mkACE2-RBD F486L complexes helped identify the key residues that facilitate changes in mkACE2 binding affinity. Additionally, the data indicated that the Y453F and F486L mutations reduced the binding affinities to some human monoclonal antibodies, and human vaccinated sera efficiently prevented infection of human cells by pseudoviruses expressing Y453F, F486L, or N501T RBD. Our findings provide an important molecular mechanism for the rapid adaptation of SARS-CoV-2 in minks and highlight the potential influence of the main mink-originating variants for humans. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a broad range of hosts. Mink-derived SARS-CoV-2 can transmit back to humans. There is an urgent need to understand the binding mechanism of mink-derived SARS-CoV-2 variants to mink receptor. In this study, we identified all mutations in the receptor-binding domain (RBD) of spike (S) protein from mink-derived SARS-CoV-2, and we demonstrated the enhanced binding affinity of mink angiotensin-converting enzyme 2 (ACE2) to most of the mink-derived RBD variants as well as important human-originating RBD variants. Cryo-electron microscopy structures revealed that the Y453F and F486L mutations enhanced the binding forces in the interaction interface. In addition, Y453F and F486L mutations reduced the binding affinities to some human monoclonal antibodies, and the SARS-CoV-2 pseudoviruses with Y453F, F486L, or N501T mutations were neutralized by human vaccinated sera. Therefore, our results provide valuable information for understanding the cross-species transmission mechanism of SARS-CoV-2.
Insights
Mutations in SARS-CoV-2 variants, particularly in mink-derived viruses, enhance binding to mink ACE2 receptors. These mutations may affect antibody binding but remain neutralized by vaccinated human sera.
Area of Science:
- Virology and Molecular Biology
- Structural Biology
- Immunology
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibits host adaptability, with documented transmission between humans and minks.
- Mutations within the spike (S) protein's receptor-binding domain (RBD) of mink-derived SARS-CoV-2 are of significant concern for cross-species transmission.
- Understanding the molecular interactions between mink-derived SARS-CoV-2 variants and mink angiotensin-converting enzyme 2 (ACE2) is crucial for public health.
Purpose of the Study:
- To investigate the binding affinities of mink-derived and human-originating SARS-CoV-2 RBD variants to the mink ACE2 receptor.
- To elucidate the structural basis for altered binding affinities using cryo-electron microscopy.
- To assess the impact of specific mutations on the efficacy of human monoclonal antibodies and vaccinated sera against SARS-CoV-2 variants.
Main Methods:
- Analysis of SARS-CoV-2 spike protein RBD mutations identified in mink-derived viruses.
- Biochemical assays to measure binding affinities between various RBD variants and mink ACE2 (mkACE2).
- Cryo-electron microscopy (cryo-EM) to determine the structures of mkACE2 complexed with specific RBD variants (Y453F, F486L).
- Assessment of binding affinities to human monoclonal antibodies and neutralization assays using human vaccinated sera against pseudoviruses.
Main Results:
- Most SARS-CoV-2 RBD variants, including mink-derived and human-originating ones, exhibited increased binding affinities to mkACE2.
- Cryo-EM structures revealed that Y453F and F486L mutations enhance binding interactions at the mkACE2-RBD interface.
- The Y453F and F486L mutations decreased binding to certain human monoclonal antibodies, but human vaccinated sera effectively neutralized pseudoviruses expressing these variants (Y453F, F486L, N501T).
Conclusions:
- Specific mutations in SARS-CoV-2 RBD facilitate enhanced binding to mink ACE2, providing a molecular mechanism for viral adaptation in minks.
- Mink-derived SARS-CoV-2 variants with mutations like Y453F and F486L show altered interactions with human antibodies.
- Despite potential immune evasion, current human vaccine-induced immunity appears capable of neutralizing key mink-associated SARS-CoV-2 variants, underscoring the importance of ongoing surveillance.
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