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- Title
Missense variants in human ACE2 strongly affect binding to SARS-CoV-2 Spike providing a mechanism for ACE2 mediated genetic risk in Covid-19: A case study in affinity predictions of interface variants.
- Authors
MacGowan, Stuart A.; Barton, Michael I.; Kutuzov, Mikhail; Dushek, Omer; van der Merwe, P. Anton; Barton, Geoffrey J.
- 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. Author summary: One of the first things the SARS-CoV-2 virus does to invade human cells is bind to a cell surface receptor called angiotensin-converting enzyme 2 (ACE2). The virus attaches to this receptor through its Spike protein and knowledge from other viruses tells us that the strength of this interaction influences how infectious and or virulent it is. We hypothesised that the Spike-ACE2 affinity might vary in people who have different amino acids in the part of ACE2 where Spike binds and consequently might be protected–or more at risk–from the virus. To test this idea, we measured the affinity of several ACE2 mutants, representing different versions found in humans, for the Spike protein and we found that some strengthened the interactions alongside others that weakened it. Most of these variants are rare, but two are present in over 1 in 1,000 individuals in certain populations and so might be important for the epidemiology of COVID-19. We then used computational methods to predict the affinity of even more ACE2 mutants than we could test in the lab and again found many that might alter this interaction. These data may help identify people who are at higher or lower risk from COVID-19.
- Subjects
ANGIOTENSIN converting enzyme; CELL receptors; MISSENSE mutation; COVID-19 pandemic; SURFACE plasmon resonance; SARS-CoV-2; CHICKEN diseases
- Publication
PLoS Computational Biology, 2022, Vol 18, Issue 3, p1
- ISSN
1553-734X
- Publication type
Article
- DOI
10.1371/journal.pcbi.1009922