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Cited by 25SARS-CoV-2 and COVID-19 ResearchAnimal Virus Infections StudiesZoonotic diseases and public health

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Sarbecovirus RBD indels and specific residues dictating multi-species ACE2 adaptiveness

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Si, Jun-Yu, Chen, Yuan-Mei, Sun, Ye-Hui, Gu, Meng-Xue, Huang, Mei-Ling, Shi, Lu-Lu, Yu, Xiao, Yang, Xiao, Xiong, Qing, Ma, Cheng-Bao, Liu, Peng, Shi, Zheng-Li, Yan, Huan·2024·Nature Communications
DOI 10.1038/s41467-024-53029-3PMC PMC11473667

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Abstract

Abstract Sarbecoviruses exhibit varying abilities in using angiotensin-converting enzyme 2 (ACE2) receptor1-3. However, a comprehensive understanding of their multi-species ACE2 adaptiveness and the underlying mechanism remains elusive, particularly for many sarbecoviruses with various receptor binding motif (RBM) insertions/deletions (indels)4-11. Here, we analyzed RBM sequences from 268 sarbecoviruses categorized into four RBM indel types. We extensively examined the capability of 14 representative sarbecoviruses and their derivatives in using ACE2 orthologues from 51 bats and five non-bat mammals. We revealed that most sarbecoviruses with longer RBMs (type-I), present broad ACE2 tropism, whereas viruses with single deletions in Region 1 (type-II) or Region 2 (type-III) generally exhibit narrow ACE2 tropism, typically favoring their hosts’ ACE2. Sarbecoviruses with double region deletions (type-IV) exhibit a complete loss of ACE2 usage. Subsequent investigations unveiled that both loop deletions and critical RBM residues significantly impact multi-species ACE2 tropism in different ways. Additionally, fine mapping based on type-IV sarbecoviruses elucidated the role of several clade-specific residues, both within and outside the RBM, in restricting ACE2 usage. Lastly, we hypothesized the evolution of sarbecovirus RBM indels and illustrated how loop length, disulfide, and adaptive mutations shape their multi-species ACE2 adaptiveness. This study provides profound insights into the mechanisms governing ACE2 usage and spillover risks of sarbecoviruses.

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Metadata

Authors
Si, J.-Y., Chen, Y.-M., Sun, Y.-H., Gu, M.-X., Huang, M.-L., Shi, L.-L., Yu, X., Yang, X., Xiong, Q., Ma, C.-B., Liu, P., Shi, Z.-L., & Yan, H.
Affiliations
  • Wuhan University (CN)
  • Chinese Academy of Sciences (CN)
Corresponding author
Yan, Huan
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-10-14
Volume
15
Issue
1
Pages
8869-8869
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-53029-3
PMC
PMC11473667
OpenAlex
W4403383740
Cited by
25
References
4
Citations by year
2026: 11 · 2025: 13 · 2024: 1
FWCI
8.65
Type
journal article
Language
en
Update notices
correction (2025-07-09)
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (32270164, 82322041, 32070160)
  • Natural Science Foundation of Hubei Province (2023AFA015)
  • Tsinghua University
  • Wuhan University
  • Fundamental Research Funds for the Central Universities (2042023kf0191, 2042022kf1188)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Zoonotic diseases and public health
Keywords
sarbecoviruses, receptor binding domain, ACE2 receptor, host tropism, spike protein, bats, SARS-CoV-2, viral evolution, receptor-binding motif, spillover risk, disulfide bonds, loop length
MeSH terms
Angiotensin-Converting Enzyme 2, Amino Acid Sequence, Animals, Binding Sites, Chiroptera, Humans, Phylogeny, Protein Binding, Receptors, Virus, RNA Viruses, INDEL Mutation, Viral Tropism, HEK293 Cells, Spike Glycoprotein, Coronavirus

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