Missense variants in human ACE2 modify binding to SARS-CoV-2 Spike

TY - UNPB

T1 - Missense variants in human ACE2 modify binding to SARS-CoV-2 Spike

AU - MacGowan, Stuart A.

AU - Barton, Michael I.

AU - Kutuzov, Mikhail

AU - Dushek, Omer

AU - Merwe, P. Anton van der

AU - Barton, Geoffrey J.

N1 - This work was supported by Biotechnology and Biological Sciences Research Council Grants (BB/J019364/1 and BB/R014752/1) and Wellcome Trust Biomedical Resources Grant (101651/Z/13/Z). OD is supported by a Wellcome Trust Senior Fellowship in Basic Biomedical Sciences (207537/Z/17/Z828).

PY - 2021/5/21

Y1 - 2021/5/21

N2 - 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.

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.

U2 - 10.1101/2021.05.21.445118

DO - 10.1101/2021.05.21.445118

M3 - Preprint

BT - Missense variants in human ACE2 modify binding to SARS-CoV-2 Spike

PB - BioRxiv

ER -