Journal Article

Mutation Y453F in the spike protein of SARS-CoV-2 enhances interaction with the mink ACE2 receptor for host adaption

Fan, Shilong, Ding, Qiang, Gong, Mingli, Zhu, Zihui, Zhong, Jin, Huang, Ailong, Long, Quanxin, Yu, Yanying, Ju, Xiaohui, Lan, Jun, Wu, Jianping, Wang, Xinquan, Ren, Wenlin, Zhang, Rong, Zhong, Guocai

2021

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: ACE2 / Adult / Aged / Amino acids / Analysis / Angiotensin converting enzyme / Angiotensin-converting enzyme 2 / Angiotensin-Converting Enzyme 2 - genetics / Angiotensin-Converting Enzyme 2 - metabolism / Animals / Binding / Binding Sites / Biology and life sciences / Clusters / Coronaviruses / COVID-19 / COVID-19 - epidemiology / COVID-19 - immunology / COVID-19 - therapy / COVID-19 - transmission / COVID-19 - virology / COVID-19 Serotherapy / Disease transmission / Diseases / Efficiency / Experiments / Female / Flow cytometry / Gene mutations / Gene sequencing / Genetic aspects / Genetic diversity / Genetic variance / Health aspects / Host Adaptation / Human performance / Humans / Hydrogen bonds / Hydrophobicity / Immunization, Passive - statistics & numerical data / Localization / Male / Mammals / Medicine and health sciences / Middle Aged / Mink - immunology / Mink - virology / Minks / Molecular Dynamics Simulation / Mustela / Mutation / Netherlands - epidemiology / Observations / Protein Binding / Proteins / Receptors / Research and Analysis Methods / Respiratory diseases / SARS-CoV-2 - genetics / SARS-CoV-2 - isolation & purification / Severe acute respiratory syndrome / Severe acute respiratory syndrome coronavirus 2 / Spike Glycoprotein, Coronavirus - genetics / Spike Glycoprotein, Coronavirus - metabolism / Spike protein / Structural analysis / Vaccine development / Vaccines / Viral diseases / Virus Internalization / Viruses / Young Adult