In:
PLOS Computational Biology, Public Library of Science (PLoS), Vol. 18, No. 3 ( 2022-3-2), p. e1009922-
Abstract:
SARS-CoV-2 Spike (Spike) binds to human angiotensin-converting enzyme 2 (ACE2) and the strength of this interaction could influence parameters relating to virulence. To explore whether population variants in ACE2 influence Spike binding and hence infection, we selected 10 ACE2 variants based on affinity predictions and prevalence in gnomAD and measured their affinities and kinetics for Spike receptor binding domain through surface plasmon resonance (SPR) at 37°C. We discovered variants that reduce and enhance binding, including three 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) binding. We also identified two variants with distinct population distributions that enhanced affinity for Spike. ACE2 p.Ser19Pro (ΔΔG = 0.59 ± 0.08 kcal mol -1 ) is predominant 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. We compared ACE2 variant affinities to published SARS-CoV-2 pseudotype infectivity data and confirmed that ACE2 variants with reduced affinity for Spike can protect cells from infection. The effect of variants with enhanced Spike affinity remains unclear, but we propose a mechanism whereby these alleles could cause greater viral spreading across tissues and cell types, as is consistent with emerging understanding regarding the interplay between receptor affinity and cell-surface abundance. Finally, we compared mCSM-PPI2 ΔΔG predictions against our SPR data to assess the utility of predictions in this system. We found that predictions of decreased binding were well-correlated with experiment and could be improved by calibration, but disappointingly, predictions of highly enhanced binding were unreliable. Recalibrated predictions for all possible ACE2 missense variants at the Spike interface were calculated and used to estimate the overall burden of ACE2 variants on Covid-19.
Type of Medium:
Online Resource
ISSN:
1553-7358
DOI:
10.1371/journal.pcbi.1009922
DOI:
10.1371/journal.pcbi.1009922.g001
DOI:
10.1371/journal.pcbi.1009922.g002
DOI:
10.1371/journal.pcbi.1009922.g003
DOI:
10.1371/journal.pcbi.1009922.g004
DOI:
10.1371/journal.pcbi.1009922.g005
DOI:
10.1371/journal.pcbi.1009922.g006
DOI:
10.1371/journal.pcbi.1009922.g007
DOI:
10.1371/journal.pcbi.1009922.t001
DOI:
10.1371/journal.pcbi.1009922.t002
DOI:
10.1371/journal.pcbi.1009922.t003
DOI:
10.1371/journal.pcbi.1009922.t004
DOI:
10.1371/journal.pcbi.1009922.s001
DOI:
10.1371/journal.pcbi.1009922.s002
DOI:
10.1371/journal.pcbi.1009922.s003
DOI:
10.1371/journal.pcbi.1009922.s004
DOI:
10.1371/journal.pcbi.1009922.s005
DOI:
10.1371/journal.pcbi.1009922.s006
DOI:
10.1371/journal.pcbi.1009922.s007
DOI:
10.1371/journal.pcbi.1009922.s008
DOI:
10.1371/journal.pcbi.1009922.s009
DOI:
10.1371/journal.pcbi.1009922.s010
DOI:
10.1371/journal.pcbi.1009922.s011
DOI:
10.1371/journal.pcbi.1009922.r001
DOI:
10.1371/journal.pcbi.1009922.r002
DOI:
10.1371/journal.pcbi.1009922.r003
DOI:
10.1371/journal.pcbi.1009922.r004
DOI:
10.1371/journal.pcbi.1009922.r005
DOI:
10.1371/journal.pcbi.1009922.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2193340-6