RT Journal Article
SR Electronic
T1 ACE2 binding is an ancestral and evolvable trait of sarbecoviruses
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.07.17.452804
DO 10.1101/2021.07.17.452804
A1 Tyler N. Starr
A1 Samantha K. Zepeda
A1 Alexandra C. Walls
A1 Allison J. Greaney
A1 David Veesler
A1 Jesse D. Bloom
YR 2021
UL http://biorxiv.org/content/early/2021/07/19/2021.07.17.452804.abstract
AB Two different sarbecoviruses have caused major human outbreaks in the last two decades1,2. Both these sarbecoviruses, SARS-CoV-1 and SARS-CoV-2, engage ACE2 via the spike receptor-binding domain (RBD)2–6. However, binding to ACE2 orthologs from humans, bats, and other species has been observed only sporadically among the broader diversity of bat sarbecoviruses7–11. Here, we use high-throughput assays12 to trace the evolutionary history of ACE2 binding across a diverse range of sarbecoviruses and ACE2 orthologs. We find that ACE2 binding is an ancestral trait of sarbecovirus RBDs that has subsequently been lost in some clades. Furthermore, we demonstrate for the first time that bat sarbecoviruses from outside Asia can bind ACE2. In addition, ACE2 binding is highly evolvable: for many sarbecovirus RBDs there are single amino-acid mutations that enable binding to new ACE2 orthologs. However, the effects of individual mutations can differ markedly between viruses, as illustrated by the N501Y mutation which enhances human ACE2 binding affinity within several SARS-CoV-2 variants of concern12 but severely dampens it for SARS-CoV-1. Our results point to the deep ancestral origin and evolutionary plasticity of ACE2 binding, broadening consideration of the range of sarbecoviruses with spillover potential.Competing Interest StatementJDB consults for Moderna on viral evolution and epidemiology and Flagship Labs 77 on deep mutational scanning. JDB may receive a share of IP revenue as an inventor on a Fred Hutchinson Cancer Research Center-optioned technology/patent (application WO2020006494) related to deep mutational scanning of viral proteins. DV is a consultant for Vir Biotechnology Inc. The Veesler laboratory has received an unrelated sponsored research agreement from Vir Biotechnology Inc.