Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection

Abstract

SARS-CoV-2 causes the recent global COVID-19 public health emergency. ACE2 is the receptor for both SARS-CoV-2 and SARS-CoV. To predict the potential host range of SARS-CoV-2, we analyzed the key residues of ACE2 for recognizing S protein. We found that most of the selected mammals including pets (dog and cat), pangolin and Circetidae mammals remained the most of key residues for association with S protein from SARS-CoV and SARS-CoV-2. The interaction interface between cat/dog/pangolin/Chinese hamster ACE2 and SARS-CoV/SARS-CoV-2 S protein was simulated through homology modeling. We identified that N82 in ACE2 showed a closer contact with SARS-CoV-2 S protein than M82 in human ACE2. Our finding will provide important insights into the host range of SARS-CoV-2 and a new strategy to design an optimized ACE2 for SARS-CoV-2 infection.

Keywords: ACE2; Host range; SARS-CoV-2; Spike protein; Structure.

Fig. 1

Alignment of RBM region of S proteins from SARS-CoV-2 and SARS-CoV. (A) Sequence alignment of RBM region of S protein from SARS-CoV-2 and SARS-CoV. ▲ represents the six key amino acids in the S protein interacting with human ACE2. For SARS-CoV, they are Y442, L472, N479, D480, T487 and Y491. The S protein sequence of SARS-CoV-2 comes from YP_009724390.1, and the S protein sequence of SARS-CoV comes from NP_828851.1. (B) Alignment of the structure of ACE2 recognition of RBD from SARS-CoV-2 and SARS-CoV. Human ACE2 (hACE2), SARS-CoV-2 RBD, and SARS-CoV RBD are in orange red, blue, and green, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Phylogenetic tree of mammalian ACE2 proteins. ACE2 sequences from a total of 42 mammals were analyzed by MEGA-X and the phylogenetic tree was constructed with JTT evolutionary model using Maximum Likelihood method. The red represents the species whose ACE2 cannot bind to S protein, and the green is the species whose ACE2 associate with S protein. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Structure simulation of SARSr-CoV RBD with ACE2 from dog, cat, pangolin and Chinese hamster. (A) Structural simulation of the protein complex of dog ACE2 and SARSr-CoV RBD. Dog ACE2, SARS-CoV-2 RBD, SARS-CoV RBD are in gold, blue, and green, respectively. (B) Structural simulation of the protein complex of cat ACE2 and SARSr-CoV RBD. Cat ACE2, SARS-CoV-2 RBD, and SARS-CoV RBD are in pulm, blue and green, respectively. (C) Structural simulation of the protein complex of pangolin ACE2 and SARSr-CoV RBD. Pangolin ACE2, SARS-CoV-2 RBD, and SARS-CoV RBD are in sandy brown, blue and green, respectively. (D) Structural simulation of the protein complex of Chinese hamster ACE2 and SARSr-CoV RBD. Chinese hamster ACE2, SARS-CoV-2 RBD, and SARS-CoV RBD are in dim gray, blue and green, respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)