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Molecular Basis of Mink ACE2 Binding to SARS-CoV-2 and Its Mink-Derived Variants.

Chao Su1,2 Juanhua He2,3 Pengcheng Han2,4 Bin Bai2,5 Dedong Li2,6 Jian Cao2 Mingxiong Tian2,7 Yu Hu2,8 Anqi Zheng2,4 Sheng Niu2,9 Qian Chen2,10 Xiaoyu Rong2,11 Yanfang Zhang2 Weiwei Li2 Jianxun Qi2 Xin Zhao2,12 Mengsu Yang1 Qihui Wang2 George Fu Gao1,2,3
Affiliations 12 institutions
  1. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
  2. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  3. College of Life Sciences, Jiangxi Science and Technology Normal University, Nanchang, China.
  4. College of Life Science and Technology, Southeast University, Nanjing, China.
  5. University of the Chinese Academy of Sciences, Beijing, China.
  6. College of Veterinary Medicine, China Agricultural University, Beijing, China.
  7. School of Life Sciences, Shanxi University, Taiyuan, China.
  8. School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
  9. College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong, China.
  10. Institutes of Physical Science and Information Technology, Anhui University, Hefei, China.
  11. School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China.
  12. CAS Center for Influenza Research and Early-Warning, Chinese Academy of Sciences, Beijing, China.
PMID 36000849 2022 J Virol eng ppublish
PubMed DOI Browse context

Article

Publication summary

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. <b>IMPORTANCE</b> 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.

ACE2 cryo-EM structure F486L mink N501T SARS-CoV-2 virus entry Y453F Angiotensin-Converting Enzyme 2 Mink Animals Antibodies, Monoclonal COVID-19 Cryoelectron Microscopy Humans Mutation Peptidyl-Dipeptidase A Protein Binding

Structured evidence records

Evidence records

5 total
Molecular Adaptation 2 records
Molecular Adaptation Extraction confidence 1.00
Key finding

Y453F and F486L mutations in the SARS-CoV-2 spike RBD enhance binding to mink ACE2 and reduce affinity to some human monoclonal antibodies, indicating molecular adaptation to mink hosts.

Virus
SARS-CoV-2
Host
Not specified
Location
Not specified
Supporting text

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.

Genes or proteins
spike; RBD
Receptors
ACE2
Mutations
Y453F; F486L
Mechanism types
receptor_binding; immune_escape
Molecular Adaptation Extraction confidence 0.95
Key finding

SARS-CoV-2 pseudoviruses with Y453F, F486L, or N501T mutations in RBD were neutralized by human vaccinated sera, demonstrating partial immune escape and host adaptation relevance.

Virus
SARS-CoV-2
Host
Not specified
Location
Not specified
Supporting text

Human vaccinated sera efficiently prevented infection of human cells by pseudoviruses expressing Y453F, F486L, or N501T RBD.

Genes or proteins
spike; RBD
Mutations
Y453F; F486L; N501T
Mechanism types
immune_escape
Spillover Event 2 records
Spillover Event Extraction confidence 0.85
Key finding

SARS-CoV-2 was transmitted bidirectionally between humans and minks, including mink-derived virus variants that infected humans.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

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. Mink-derived SARS-CoV-2 can transmit back to humans.

Method
cryo-electron microscopy; pseudovirus assay
Transmission direction
animal-to-human
Spillover Event Extraction confidence 0.85
Key finding

Evidence supports human-to-mink transmission of SARS-CoV-2.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted between humans and minks.

Method
cryo-electron microscopy; pseudovirus assay
Transmission direction
human-to-animal
Receptor Usage 1 records
Receptor Usage Extraction confidence 1.00
Key finding

SARS‑CoV‑2 mink‑derived receptor‑binding domain variants Y453F and F486L showed enhanced binding affinity to mink ACE2 as determined by binding and cryo‑EM structural analysis.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

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 and mkACE2‑RBD F486L complexes helped identify the key residues that facilitate changes in mkACE2 binding affinity.

Method
binding assay; cryo-electron microscopy
Receptors
ACE2