Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility

Eric W. Stawiski; Devan Diwanji; Kushal Suryamohan; Ravi Gupta; Frederic A. Fellouse; J. Fah Sathirapongsasuti; Jiang Liu; Ying-Ping Jiang; Aakrosh Ratan; Monika Mis; Devi Santhosh; Sneha Somasekar; Sangeetha Mohan; Sameer Phalke; Boney Kuriakose; Aju Antony; Jagath R. Junutula; Stephan C. Schuster; Natalia Jura; Somasekar Seshagiri

Included among the ACE2 polymorphic variants that increase ACE2/S-protein interaction are S19P, I21V, E23K, K26R, K26E, T27A, N64K, T92I, Q102P, M383T and Table 2 Figure 3 ). Among these, the T92I polymorphism stands out in particular because it is part of a NxT/S (where x is any amino acid except proline) consensus N-glycosylation motif (Gavel and von Heijne, 1990) where N90 is the site of N-glycan addition. The ACE2 NxT/S motif, while conserved in 96 out of 296 jawed vertebrate with ACE2 sequence available is absent or altered in several species, including the civet cat (Paguma larvata) and several bat species where residue N90 is mutated, a proline is present at position 91 or the T92 is altered to any amino acid except serine (Figure 1d (Demogines et al., 2012; Gavel and von Heijne, 1990; Li et al., 2005b) . These ACE2 variations are expected to abolish glycosylation at N90 (Gavel and von Heijne, 1990) . Furthermore, a mutation that altered the NxT/S motif in human 7 ACE2 to a civet ACE2-like sequence (90-NLTV-93 to DAKI), expected to abolish the Nglycosylation, increased the SARS-CoV infectivity and S-protein binding (Figure 1d ) (Li et al., 2005b) . The T92I mutant we identified showed a strong enrichment in the sequencing-based screen for S-protein binders (Procko, 2020) . Considering these observations, we conclude that the T92I mutation increases the ACE2/S-protein binding affinity rendering individuals harboring this mutation more susceptibility to the virus.