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Mutation Y453F in the spike protein of SARS-CoV-2 enhances interaction with the mink ACE2 receptor for host adaption.
PLoS Pathog. 2021 11; 17(11):e1010053.PP

Abstract

COVID-19 patients transmitted SARS-CoV-2 to minks in the Netherlands in April 2020. Subsequently, the mink-associated virus (miSARS-CoV-2) spilled back over into humans. Genetic sequences of the miSARS-CoV-2 identified a new genetic variant known as "Cluster 5" that contained mutations in the spike protein. However, the functional properties of these "Cluster 5" mutations have not been well established. In this study, we found that the Y453F mutation located in the RBD domain of miSARS-CoV-2 is an adaptive mutation that enhances binding to mink ACE2 and other orthologs of Mustela species without compromising, and even enhancing, its ability to utilize human ACE2 as a receptor for entry. Structural analysis suggested that despite the similarity in the overall binding mode of SARS-CoV-2 RBD to human and mink ACE2, Y34 of mink ACE2 was better suited to interact with a Phe rather than a Tyr at position 453 of the viral RBD due to less steric clash and tighter hydrophobic-driven interaction. Additionally, the Y453F spike exhibited resistance to convalescent serum, posing a risk for vaccine development. Thus, our study suggests that since the initial transmission from humans, SARS-CoV-2 evolved to adapt to the mink host, leading to widespread circulation among minks while still retaining its ability to efficiently utilize human ACE2 for entry, thus allowing for transmission of the miSARS-CoV-2 back into humans. These findings underscore the importance of active surveillance of SARS-CoV-2 evolution in Mustela species and other susceptible hosts in order to prevent future outbreaks.

Authors+Show Affiliations

Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China.Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, China.Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China.Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China.Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China.Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China.Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China.Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China.Unit of Viral Hepatitis, Institut Pasteur of Shanghai, CAS Key Laboratory of Molecular Virology and Immunology, Chinese Academy of Sciences, Shanghai, China.Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Biosafety Level 3 Laboratory, Fudan University, Shanghai, China.Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, China.Shenzhen Bay Laboratory, Shenzhen, China. School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.Key Laboratory of Molecular Biology on Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China.Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing, China.Center for Infectious Disease Research, School of Medicine, Tsinghua University, Beijing, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34748603

Citation

Ren, Wenlin, et al. "Mutation Y453F in the Spike Protein of SARS-CoV-2 Enhances Interaction With the Mink ACE2 Receptor for Host Adaption." PLoS Pathogens, vol. 17, no. 11, 2021, pp. e1010053.
Ren W, Lan J, Ju X, et al. Mutation Y453F in the spike protein of SARS-CoV-2 enhances interaction with the mink ACE2 receptor for host adaption. PLoS Pathog. 2021;17(11):e1010053.
Ren, W., Lan, J., Ju, X., Gong, M., Long, Q., Zhu, Z., Yu, Y., Wu, J., Zhong, J., Zhang, R., Fan, S., Zhong, G., Huang, A., Wang, X., & Ding, Q. (2021). Mutation Y453F in the spike protein of SARS-CoV-2 enhances interaction with the mink ACE2 receptor for host adaption. PLoS Pathogens, 17(11), e1010053. https://doi.org/10.1371/journal.ppat.1010053
Ren W, et al. Mutation Y453F in the Spike Protein of SARS-CoV-2 Enhances Interaction With the Mink ACE2 Receptor for Host Adaption. PLoS Pathog. 2021;17(11):e1010053. PubMed PMID: 34748603.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutation Y453F in the spike protein of SARS-CoV-2 enhances interaction with the mink ACE2 receptor for host adaption. AU - Ren,Wenlin, AU - Lan,Jun, AU - Ju,Xiaohui, AU - Gong,Mingli, AU - Long,Quanxin, AU - Zhu,Zihui, AU - Yu,Yanying, AU - Wu,Jianping, AU - Zhong,Jin, AU - Zhang,Rong, AU - Fan,Shilong, AU - Zhong,Guocai, AU - Huang,Ailong, AU - Wang,Xinquan, AU - Ding,Qiang, Y1 - 2021/11/08/ PY - 2021/07/27/received PY - 2021/10/20/accepted PY - 2021/11/18/revised PY - 2021/11/9/pubmed PY - 2021/11/30/medline PY - 2021/11/8/entrez SP - e1010053 EP - e1010053 JF - PLoS pathogens JO - PLoS Pathog VL - 17 IS - 11 N2 - COVID-19 patients transmitted SARS-CoV-2 to minks in the Netherlands in April 2020. Subsequently, the mink-associated virus (miSARS-CoV-2) spilled back over into humans. Genetic sequences of the miSARS-CoV-2 identified a new genetic variant known as "Cluster 5" that contained mutations in the spike protein. However, the functional properties of these "Cluster 5" mutations have not been well established. In this study, we found that the Y453F mutation located in the RBD domain of miSARS-CoV-2 is an adaptive mutation that enhances binding to mink ACE2 and other orthologs of Mustela species without compromising, and even enhancing, its ability to utilize human ACE2 as a receptor for entry. Structural analysis suggested that despite the similarity in the overall binding mode of SARS-CoV-2 RBD to human and mink ACE2, Y34 of mink ACE2 was better suited to interact with a Phe rather than a Tyr at position 453 of the viral RBD due to less steric clash and tighter hydrophobic-driven interaction. Additionally, the Y453F spike exhibited resistance to convalescent serum, posing a risk for vaccine development. Thus, our study suggests that since the initial transmission from humans, SARS-CoV-2 evolved to adapt to the mink host, leading to widespread circulation among minks while still retaining its ability to efficiently utilize human ACE2 for entry, thus allowing for transmission of the miSARS-CoV-2 back into humans. These findings underscore the importance of active surveillance of SARS-CoV-2 evolution in Mustela species and other susceptible hosts in order to prevent future outbreaks. SN - 1553-7374 UR - https://www.unboundmedicine.com/medline/citation/34748603/Mutation_Y453F_in_the_spike_protein_of_SARS_CoV_2_enhances_interaction_with_the_mink_ACE2_receptor_for_host_adaption_ DB - PRIME DP - Unbound Medicine ER -