Predicting the angiotensin converting enzyme 2 (ACE2) utilizing capability as the receptor of SARS-CoV-2

Abstract

SARS-CoV-2, the newly identified human coronavirus causing severe pneumonia pandemic, was probably originated from Chinese horseshoe bats. However, direct transmission of the virus from bats to humans is unlikely due to lack of direct contact, implying the existence of unknown intermediate hosts. Angiotensin converting enzyme 2 (ACE2) is the receptor of SARS-CoV-2, but only ACE2s of certain species can be utilized by SARS-CoV-2. Here, we evaluated and ranked the receptor-utilizing capability of ACE2s from various species by phylogenetic clustering and sequence alignment with the currently known ACE2s utilized by SARS-CoV-2. As a result, we predicted that SARS-CoV-2 tends to utilize ACE2s of various mammals, except murines, and some birds, such as pigeon. This prediction may help to screen the intermediate hosts of SARS-CoV-2.

Keywords: Angiotensin converting enzyme 2 (ACE2); Coronavirus; Phylogenetic analysis; Receptor utilization; SARS-CoV-2.

Fig. 1

Part of the phylogenetic tree of ACE2s from selected species. The tree was constructed on the whole aa sequences of ACE2s using NJ method by MEGA7 with 1000 bootstrap replicates. The utilizing capability of every ACE2 was marked with different labelled as indicated. The ACE2 sequence of Homo sapiens (Q9BYF1), Rhinolophus sinicus (U5WHY8), Paguma Larvata (Q56NL1), Sus scrofa (K7GLM4) and Mus musculus (Q8R0I0) were downloaded from UniProt Knowledgebase. The rest were downloaded from GenBank as follows: Capra hircus (AHI85757.1), Ovis aries (XP_011961657.1), Bos taurus (XP_005228485.1), Bubalus bubalis (XP_006041602.1), Equus caballus (XP_001490241.1), Pteropus alecto (XP_006911709.1), Manis javanica (XP_017505752.1), Mustela ermine (XP_032187679.1), Canis lupus dingo (XP_025292934.1), Felis catus (AAX59005.1), Lynx Canadensis (XP_030160839.1), Dasypus novemcinctus (XP_004449124.1), Rattus norvegicus (NP_001012006.1), Grammomys surdaster (XP_028617962.1), Mus caroli (XP_021009138.1), Nestor notabilis (XP_021009138.1), Merops nubicus (XP_010012481.1), Egretta garzetta (XP_009638257.1), Apaloderma vittatum (XP_009867056.1), Colius striatus (XP_009082150.1), Columba livia (PKK30539.1), Rotobothrops mucrosquamatus (XP_029140508.1).

Fig. 2

Critical amino acid sites predicted for the utilization of SARS-CoV-2. (A) The structure of the binding complex of human ACE2 and SARS-CoV-2 RBD. The structure was adapted from Protein Data Bank (PDB ID: 6VW1) and the aa residues distinct in mouse ACE2 (T20, Y83, S218, A246, K353, P426 and T593) are labelled with red. N636, A714, R716 and A774 are not included in the structure, since they are too far away from the interface and were not crystallized in the structure analysis. (B) The aa sequences of Homo sapiens (Human), Rhinolophus sinicus (Bat), Paguma Larvata (Civet), Sus scrofa (swine) and Mus musculus (mouse) ACE2s were aligned. The critical sites identified by the alignment were highlighted with yellow background. The critical sites reported in SARS-CoV binding are highlighted with red font.