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Review
. 2015 Aug;23(8):468-78.
doi: 10.1016/j.tim.2015.06.003. Epub 2015 Jul 21.

Bat-to-human: spike features determining 'host jump' of coronaviruses SARS-CoV, MERS-CoV, and beyond

Guangwen Lu  1 , Qihui Wang  2 , George F Gao  3
Affiliations
Review

Bat-to-human: spike features determining 'host jump' of coronaviruses SARS-CoV, MERS-CoV, and beyond

Guangwen Lu et al. Trends Microbiol. 2015 Aug.

Abstract

Both severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are zoonotic pathogens that crossed the species barriers to infect humans. The mechanism of viral interspecies transmission is an important scientific question to be addressed. These coronaviruses contain a surface-located spike (S) protein that initiates infection by mediating receptor-recognition and membrane fusion and is therefore a key factor in host specificity. In addition, the S protein needs to be cleaved by host proteases before executing fusion, making these proteases a second determinant of coronavirus interspecies infection. Here, we summarize the progress made in the past decade in understanding the cross-species transmission of SARS-CoV and MERS-CoV by focusing on the features of the S protein, its receptor-binding characteristics, and the cleavage process involved in priming.

Keywords: MERS-CoV; SARS-CoV; coronavirus; interspecies transmission; spike (S); viral and host determinants.

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Figures

Figure 1
Figure 1
Severe acute respiratory syndrome coronavirus (SARS-CoV) spike features. (A) Schematic representation of the SARS-CoV spike protein (S). The individual components of S that were either experimentally characterized in previous studies – including receptor-binding domain (RBD), fusion peptide (FP), internal fusion peptide (IFP), heptad repeat 1/2 (HR1/2), and pretransmembrane domain (PTM) , , – or are based on bioinformatics analyses, for example, N-terminal domain (NTD), are marked with the boundary-residue numbers listed below. The S1/S2 cleavage sites and the S2’-recognition site are highlighted. Other abbreviations: SP, signal peptide; TM, transmembrane domain; and CP, cytoplasmic domain. (B) Atomic structures of SARS-CoV spike RBD, FP, IFP, HR1/HR2 complex, and PTM (from left to right). The crystal structures of RBD (core subdomain in green and external subdomain in magenta) and the six-helix bundle fusion core (consisting of three HR1/HR2 helical hairpins in green, cyan, and magenta, respectively) are shown as ribbons, while the solution NMR structures of FP, IFP, and PTM are contoured using the electrostatic surface. (C) The complex structure between SARS-CoV RBD and its receptor ACE2. The core and external subdomains of RBD and the N- and C-terminal lobes of ACE2 are colored green, magenta, cyan, and orange, respectively. (D) The amino acid interactions at the RBD–ACE2 interface. According to a previous study , this binding network involves at least 18 residues in the receptor and 14 residues in SARS-CoV RBD, which are listed and connected with solid lines. Black lines indicate van der Waals contacts, and red lines represent H-bond or salt-bridge interactions.
Figure 2
Figure 2
Middle East respiratory syndrome coronavirus (MERS-CoV) spike features. (A) Schematic representation of the MERS-CoV spike protein. The boundaries for the individual components, as well as the S1/S2 and S2’ cleavage sites, are marked. Abbreviations: SP, signal peptide; NTD, N-terminal domain; RBD, receptor-binding domain; FP, fusion peptide; IFP, internal fusion peptide; HR1/2, heptad repeat 1/2; PTM, pre-transmembrane domain; TM, transmembrane domain; and CP, cytoplasmic domain. Question marks highlight the fusion peptides (FP, IFP, and PTM) of MERS-CoV that still await structural and functional characterization. (B) Crystal structures of the MERS-CoV spike RBD and HR1/HR2 fusion core. Left panel: the RBD structure with its core subdomain highlighted in green and external subdomain in magenta. Middle-left panel: a structural superimposition between MERS-CoV RBD (core and external subdomains in green and magenta, respectively) and severe acute respiratory syndrome coronavirus (SARS-CoV) RBD (in gray). Middle-right panel: the fusion core structure with the three HR1/HR2 chains in green, cyan, and magenta, respectively. Right panel: sequence comparison between SARS-CoV and MERS-CoV highlighting the spike regions of SARS-CoV FP, IFP, and PTM, respectively. Important hydrophobic residues are marked in boxes. (C) The complex structure between MERS-CoV RBD and the receptor CD26/DPP4. MERS-CoV RBD is colored as in panel (B), and the receptor is highlighted in cyan for the β-propeller domain and in orange for the α/β-hydrolase domain, respectively. The inter-blade helix referred to in the text is marked. (D) Atomic binding-network between MERS-CoV RBD and CD26 . The RBD–CD26 interface includes 13 amino acids from the receptor and 18 residues from the virus RBD, which are individually connected with either black lines, for van der Waals contacts, or red lines, for H-bond or salt-bridge interactions. The CD26 residue N229 contributes to the RBD-binding via its linked sugar moieties rather than directly engaging RBD, and is therefore highlighted in yellow.
Figure 3
Figure 3
Bat coronavirus (BatCoV) HKU4 spike features. (A) Schematic representation of the HKU4 spike protein. The listed component boundaries are mostly defined according to the bioinformatics analyses, except for the RBD which has been experimentally characterized . The cleavage sites for S1/S2 and S2’ were predicted based on the homology sequence comparison with other coronaviruses and are therefore labeled with question marks. Abbreviations: SP, signal peptide; NTD, N-terminal domain; RBD, receptor-binding domain; HR1/2, heptad repeat 1/2; TM, transmembrane domain; and CP, cytoplasmic domain. (B) Crystal structure of HKU4 RBD. The external and core subdomains are colored magenta and green, respectively. (C) Complex structure between HKU4 RBD and human CD26. The coloring scheme is: RBD core, green; RBD external, magenta; receptor β-propeller domain, cyan; and receptor α/β-hydrolase domain, orange. (D) The HKU4 RBD is suboptimal for CD26 interaction compared to Middle East respiratory syndrome coronavirus (MERS-CoV) RBD . The 18 CD26-interfacing residues in MERS-CoV RBD, as listed in Figure 2D, were individually compared with the equivalent amino acids in HKU4 RBD. The numbers highlight the van der Waals contacts each residue can provide for interacting with CD26. ‘>’ indicates that the MERS-CoV residues are better adapted for CD26-binding, and conversely, ‘<’ implies that the HKU4 amino acids are better adapted. The residue differences are highlighted with red arrows.
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