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

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

Publication date: Oct 14, 2024

Our comprehensive understanding of the multi-species ACE2 adaptiveness of sarbecoviruses remains elusive, particularly for those with various receptor binding motif (RBM) insertions/deletions (indels). Here, we analyzed RBM sequences from 268 sarbecoviruses categorized into four RBM indel types. We examined the ability of 20 representative sarbecovirus Spike glycoproteins (S) and derivatives in utilizing ACE2 from various bats and several other mammalian species. We reveal that sarbecoviruses with long RBMs (type-I) can achieve broad ACE2 tropism, whereas viruses with single deletions in Region 1 (type-II) or Region 2 (type-III) exhibit narrower ACE2 tropism. Sarbecoviruses with double region deletions (type-IV) completely lost ACE2 usage, which is restricted by clade-specific residues within and outside RBM. Lastly, we propose the evolution of sarbecovirus RBM indels and illustrate how loop lengths, disulfide, and residue determinants shape multi-species ACE2 adaptiveness. This study provides profound insights into the mechanisms governing ACE2 usage and spillover risks of sarbecoviruses.

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Concepts Keywords
Ace2 Amino Acid Sequence
Bats Angiotensin-Converting Enzyme 2
Elusive Angiotensin-Converting Enzyme 2
Mammalian Animals
Sarbecoviruses Binding Sites
Chiroptera
HEK293 Cells
Humans
INDEL Mutation
Phylogeny
Protein Binding
Receptors, Virus
Receptors, Virus
RNA Viruses
Spike Glycoprotein, Coronavirus
Spike Glycoprotein, Coronavirus
Viral Tropism

Semantics

Type Source Name
drug DRUGBANK (S)-Des-Me-Ampa
disease MESH Severe Acute Respiratory Syndrome
disease MESH COVID 19 pandemic
disease IDO host
drug DRUGBANK Amino acids
disease IDO assay
drug DRUGBANK Fenamole
drug DRUGBANK Esomeprazole
disease IDO process
drug DRUGBANK Piroxicam
disease MESH point mutation
disease MESH infection
drug DRUGBANK Aminacrine
disease IDO infectivity
disease IDO cell
drug DRUGBANK Glycine

Original Article

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