OmniVira

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.
PMID36000849 DOI10.1128/jvi.00814-22 Year2022 Journal Journal of virology J Virol Languageeng Statusppublish

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.

Supporting text Virus Host Location
ACE2 54 cryo-EM structure 9 F486L 1 mink 58 N501T 1 SARS-CoV-2 550 virus entry 10 Y453F 1 Angiotensin-Converting Enzyme 2 177 Mink 48 Animals 1948 Antibodies, Monoclonal 26 COVID-19 425 Cryoelectron Microscopy 37 Humans 1440 Mutation 209 Peptidyl-Dipeptidase A 57 Protein Binding 193 SARS-CoV-2 453 Spike Glycoprotein, Coronavirus 274 SARS-CoV-2 variants 86 spike protein, SARS-CoV-2 157

Evidence records

3 total
Functional Mechanism
3 records · 2 evidence types
Evidence type Receptor Usage
1 records
OVE6260 Receptor Usage
Key finding

SARS-CoV-2 RBD variants derived from mink and from humans show enhanced binding affinity to the mink ACE2 receptor.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
American mink Neogale vison Experimental system human Homo sapiens Experimental system
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. 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).

Method
binding assay | cryo-electron microscopy
Receptors
mink ACE2 | ACE2
Evidence type Molecular Adaptation
2 records
OVE6264 Molecular Adaptation
Key finding

Structural analysis revealed that Y453F and F486L substitutions strengthen the binding interface between mink ACE2 and SARS-CoV-2 RBD.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
Not specified
Location
Not specified
Supporting text

Cryo-electron microscopy structures revealed that the Y453F and F486L mutations enhanced the binding forces in the interaction interface.

Genes or proteins
spike | RBD
Receptors
mink ACE2
Mutations
Y453F | F486L
Mechanism types
receptor binding | host-range expansion
OVE6262 Molecular Adaptation
Key finding

SARS-CoV-2 spike RBD mutations Y453F and F486L reduced binding to human monoclonal antibodies, indicating immune-escape related adaptation.

Virus
Severe acute respiratory syndrome coronavirus 2
Host
Not specified
Location
Not specified
Supporting text

The data indicated that the Y453F and F486L mutations reduced the binding affinities to some human monoclonal antibodies.

Genes or proteins
spike | RBD
Host factors
human monoclonal antibodies
Mutations
Y453F | F486L
Mechanism types
immune escape