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. 2020 Jun;92(6):595-601.
doi: 10.1002/jmv.25726. Epub 2020 Mar 11.

Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2

Zhixin Liu  1   2 , Xiao Xiao  1 , Xiuli Wei  1 , Jian Li  1 , Jing Yang  1 , Huabing Tan  1 , Jianyong Zhu  1 , Qiwei Zhang  3   4 , Jianguo Wu  2   3 , Long Liu  1
Affiliations

Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2

Zhixin Liu et al. J Med Virol. 2020 Jun.

Abstract

From the beginning of 2002 and 2012, severe respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) crossed the species barriers to infect humans, causing thousands of infections and hundreds of deaths, respectively. Currently, a novel coronavirus (SARS-CoV-2), which has become the cause of the outbreak of Coronavirus Disease 2019 (COVID-19), was discovered. Until 18 February 2020, there were 72 533 confirmed COVID-19 cases (including 10 644 severe cases) and 1872 deaths in China. SARS-CoV-2 is spreading among the public and causing substantial burden due to its human-to-human transmission. However, the intermediate host of SARS-CoV-2 is still unclear. Finding the possible intermediate host of SARS-CoV-2 is imperative to prevent further spread of the epidemic. In this study, we used systematic comparison and analysis to predict the interaction between the receptor-binding domain (RBD) of coronavirus spike protein and the host receptor, angiotensin-converting enzyme 2 (ACE2). The interaction between the key amino acids of S protein RBD and ACE2 indicated that, other than pangolins and snakes, as previously suggested, turtles (Chrysemys picta bellii, Chelonia mydas, and Pelodiscus sinensis) may act as the potential intermediate hosts transmitting SARS-CoV-2 to humans.

Keywords: Coronavirus Disease 2019 (COVID-19); SARS-CoV-2; SARS-CoV-2 spike protein (S); angiotensin-converting enzyme 2 (ACE2); receptor-binding domain (RBD) of coronavirus.

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Conflict of interest statement

The authors declare that there are no conflict of interests.

Figures

Figure 1
Figure 1
Structural diagrams of spike glycoproteins of SARS‐CoV, MERS‐CoV, and SARS‐CoV‐2. All spike proteins of coronaviruses contain S1 subunit and S2 subunit, which were divided by the S cleavage sites. FP, fusion peptide; HR, heptad repeat 1 and heptad repeat 2; RBD, receptor‐binding domain, contains core binding motif in the external subdomain; SP, signal peptide
Figure 2
Figure 2
Phylogenetic analysis of sequences of coronavirus spike glycoproteins. The sequences of spike glycoproteins of SARS‐CoV‐2, bat SARS‐like CoV, pangolin SARS‐like CoV, and SARS‐CoV were analyzed. The red stars indicate pangolin SARS‐like CoV and bat SARS‐like CoV. Host flags are marked after the clusters. SARS‐CoV‐2, severe respiratory syndrome coronavirus‐2
Figure 3
Figure 3
Sequence alignments of the receptor‐binding domain (RBD) of coronavirus spike glycoproteins. The amino acid sequences of RBD of severe respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), pangolin SARS‐like CoV, bat SARS‐like CoV, and SARS‐CoV were aligned. The sequence identities among SARS‐CoV‐2, pangolin SARS‐like CoV SRR10168377, and bat SARS‐like CoV RaTG13 are marked. Arrows show the key residues in the interface binding to ACE2. Arrows indicate the critical binding residues for interaction between coronaviruses spike and receptor, triangle marks the ACE2‐contacting residues on spike RBD. *The unified amino acids in the same sites of all aligned sequences
Figure 4
Figure 4
The binding of receptor‐binding domain (RBD) external subdomain of spike glycoprotein with receptor ACE2. A, Structure comparison of stimulated SARS‐CoV‐2 spike and SARS‐CoV spike glycoprotein (PDB: 5 × 58), SARS‐CoV‐2 spike is shown in red and SARS‐CoV spike is shown in green. RBD contained external subdomain marked in the box. B, The binding model of SARS‐CoV‐2 spike (lower) with human receptor (upper). The possible residues in the interface of SARS‐CoV‐2 spike are shown as sticks. C, Human ACE2 critical for the binding with SARS‐CoV‐2 spike RBD is shown. The key residues located in the interface of ACE2 possibly in combination with spike RBD are shown as a sphere and colored
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