Receptor recognition and cross-species infections of SARS coronavirus

Abstract

Receptor recognition is a major determinant of the host range, cross-species infections, and pathogenesis of the severe acute respiratory syndrome coronavirus (SARS-CoV). A defined receptor-binding domain (RBD) in the SARS-CoV spike protein specifically recognizes its host receptor, angiotensin-converting enzyme 2 (ACE2). This article reviews the latest knowledge about how RBDs from different SARS-CoV strains interact with ACE2 from several animal species. Detailed research on these RBD/ACE2 interactions has established important principles on host receptor adaptations, cross-species infections, and future evolution of SARS-CoV. These principles may apply to other emerging animal viruses, including the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV). This paper forms part of a series of invited articles in Antiviral Research on "From SARS to MERS: 10years of research on highly pathogenic human coronaviruses".

Keywords: Coronavirus; Middle East respiratory syndrome; Severe acute respiratory syndrome; Spike protein; Virus evolution.

Fig. 1

Structure of the SARS-CoV spike protein complexed with its receptor ACE2. (A) Schematic domain structure of SARS-CoV spike protein. NTD: N-terminal domain. RBM: receptor-binding motif. TM: transmembrane anchor. IC: intracellular tail. (B) Overall structure of trimeric SARS-CoV spike protein complexed with ACE2, including both schematic topology of the spike protein (left) and negative-stain electron micropic images of the spike protein ectodomain with (upper right) or without a bound ACE2 (lower right). (C) Crystal structure of SARS-CoV RBD (i.e., S1 C-domain) complexed with ACE2. ACE2 is in green, RBD core structure in cyan, and RBM in red. Figure adapted from (Li et al., 2006a, Li et al., 2005a).

Fig. 2

Receptor and RBD residues that play important roles in the host range and cross-species infections of SARS-CoV. (A) Alignment of ACE2 residues from different animal species that are critical for the host range of SARS-CoV. The GenBank accession numbers are AY623811 (human ACE2), AY881174 (civet ACE2), AY881244 (rat ACE2), EF408740 (mouse ACE2), and GQ999937 (bat ACE2). ^∗ refers to an N-linked glycosylation site at the indicated position. (B) Alignment of RBD residues from different SARS-CoV strains that have undergone naturally selected mutations. The GenBank accession numbers are AAP41037 (hTor02 spike), AY304488 (cSz02 genome), AAS10463 (hcGd03 spike), ABF68956 (cHb05 spike), and AAY88866 (bHKU05 spike). (C) Distribution of the above RBD residues at the interface of SARS-CoV RBD and ACE2. Figure adapted from (Li, 2008, Wu et al., 2012).

Fig. 3

Structural basis for the civet-to-human jump and human-to-human transmission of SARS-CoV. (A)–(D) Structural details of the interfaces between ACE2 from human or civet and RBD from different viral strains. Figure adapted from (Li, 2008).

Fig. 4

Structural basis for SARS-CoV adaptations to human or civet receptor. (A) Summary of host receptor adaptation by SARS-CoV. Listed are adaptations of RBM residues to human or civet ACE2. Arrows point from less well adapted residues to better adapted residues. Double arrows connect equally well adapted residues. (B) Detailed structure of the hTor02 RBD/human ACE2 interface. ACE2 residues are in green, SARS-CoV residues that underwent mutation are in magenta, and SARS-CoV residues that played significant roles in the mutations are in cyan. Figure adapted from (Wu et al., 2012).

Fig. 5

Structural basis for the major species barriers between humans and mice, rats, or bats for SARS-CoV infections. (A)–(D) Structural details of the interfaces between ACE2 from mouse, rat or bat and RBD from human SARS-CoV strain hTor02. Figure adapted from (Hou et al., 2010, Li et al., 2005a).

Fig. 6

Summary of host range and cross-species infections of SARS-CoV. RBD mutations that overcame species barriers for the cross-species infections of SARS-CoV are in red and labeled as “+”. Residue changes in ACE2 that form species barriers and disfavor the cross-species infections of SARS-CoV are in green and labeled as “−”.

Fig. 7

Structure-based prediction of future SARS-CoV evolution. Listed are SARS-CoV strains, critical RBD residues, and binding affinities for human or civet ACE2. Arrows suggest directions of SARS-CoV evolution.