ACE2 binding is an ancestral and evolvable trait of sarbecoviruses

Abstract

Two different sarbecoviruses have caused major human outbreaks in the last two decades. Both these sarbecoviruses, SARS-CoV-1 and SARS-CoV-2, engage ACE2 via the spike receptor-binding domain (RBD). However, binding to ACE2 orthologs from humans, bats, and other species has been observed only sporadically among the broader diversity of bat sarbecoviruses. Here, we use high-throughput assays 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 concern 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.

Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift

“…These mAbs bind to epitopes overlapping with the RBM ( Fig. 3a ) which is structurally and evolutionary plastic 42 , as illustrated by the accumulation of mutations throughout the pandemic and the diversity of this subdomain among ACE2-utilizing sarbecoviruses 43 . Combining two such ACE2 blocking mAbs provides greater resistance to variant viruses that carry RBM mutations 32 .…”

Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function

“…Despite the observation that, even among sarbecoviruses, BA.1 mutations seen in cluster regions 1, 2 and 3 are only rarely seen, the instances where they do occur might be illuminating. For example, among the bat-infecting sarbecoviruses, the BA.1 S/G339D substitution (in cluster region 1) has primarily to date been found among the bat-infecting viruses within a clade (Figure 6) that does not use ACE2 as a cell entry receptor 34 . The change in receptor binding function in these viruses is, however, most likely due to two RBM deletions that are also specific to this clade.…”

Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift

“…They bind to epitopes overlapping with the RBM (Fig. 3a) which is structurally and 38 , as illustrated by the accumulation of mutations throughout the pandemic and the genetic diversity of this subdomain among ACE2-utilizing sarbecoviruses 39 . Combining two such ACE2 blocking mAbs can provide greater resistance to variant viruses that carry RBM mutations 31 .…”