RT Journal Article
SR Electronic
T1 Missense variants in human ACE2 modify binding to SARS-CoV-2 Spike
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.21.445118
DO 10.1101/2021.05.21.445118
A1 Stuart A. MacGowan
A1 Michael I. Barton
A1 Mikhail Kutuzov
A1 Omer Dushek
A1 P. Anton van der Merwe
A1 Geoffrey J. Barton
YR 2021
UL http://biorxiv.org/content/early/2021/05/21/2021.05.21.445118.abstract
AB SARS-CoV-2 infection begins with the interaction of the SARS-CoV-2 Spike (Spike) and human angiotensin-converting enzyme 2 (ACE2). To explore whether population variants in ACE2 might influence Spike binding and hence infection, we selected 10 ACE2 variants based on affinity predictions and prevalence in gnomAD and measured their affinities for Spike receptor binding domain through surface plasmon resonance (SPR). We discovered variants that enhance and reduce binding, including two variants with distinct population distributions that enhanced affinity for Spike. ACE2 p.Ser19Pro (ΔΔG = ± 0.59 0.08 kcal mol−1) is often seen in the gnomAD African cohort (AF = 0.003) whilst p.Lys26Arg (ΔΔG = 0.26 0.09 kcal mol−1) is predominant in the Ashkenazi Jewish (AF = 0.01) and European non-Finnish (AF = 0.006) cohorts. Carriers of these alleles may be more susceptible to infection or severe disease and these variants may influence the global epidemiology of Covid-19. We also identified three rare ACE2 variants that strongly inhibited (p.Glu37Lys, ΔΔG = −1.33 ± 0.15 kcal mol−1 and p.Gly352Val, predicted ΔΔG = −1.17 kcal mol−1) or abolished (p.Asp355Asn) Spike binding. These variants may confer resistance to infection. Finally, we calibrated the mCSM-PPI2 ΔΔG prediction algorithm against our SPR data, give new predictions for all possible ACE2 missense variants at the Spike interface and estimate the overall burden of ACE2 variants on Covid-19 phenotypes.Competing Interest StatementAvdW declares ownership of shares in BioNTech SE.