Molecular diversity of coronavirus host cell entry receptors

Abstract

Coronaviruses are a group of viruses causing disease in a wide range of animals, and humans. Since 2002, the successive emergence of bat-borne severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), swine acute diarrhea syndrome coronavirus (SADS-CoV) and SARS-CoV-2 has reinforced efforts in uncovering the molecular and evolutionary mechanisms governing coronavirus cell tropism and interspecies transmission. Decades of studies have led to the discovery of a broad set of carbohydrate and protein receptors for many animal and human coronaviruses. As the main determinant of coronavirus entry, the spike protein binds to these receptors and mediates membrane fusion. Prone to mutations and recombination, spike evolution has been studied extensively. The interactions between spike proteins and their receptors are often complex and despite many advances in the field, there remains many unresolved questions concerning coronavirus tropism modification and cross-species transmission, potentially leading to delays in outbreak responses. The emergence of SARS-CoV-2 underscores the need to address these outstanding issues in order to better anticipate new outbreaks. In this review, we discuss the latest advances in the field of coronavirus receptors emphasizing on the molecular and evolutionary processes that underlie coronavirus receptor usage and host range expansion.

Keywords: coronavirus; host cell receptor; host tropism; pathogenesis; severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2); virus entry.

Figure 1.

General features of the coronavirus spike protein. (A) Diagram of coronavirus virion with schematic of genome organization (based on MHV) and domains of the coronavirus spike protein. For the genome schematic, purple boxes represent ORF 1a and ORF 1b, which encode the replicase polyproteins pp1a and pp1ab. Blue boxes indicate genes encoding accessory proteins (ns2, ns4a, ns4b and ns5a), while green boxes indicate structural proteins. Abbreviations used: HE, hemagglutinin esterase; S, spike protein; E, envelope protein; M, membrane protein; N, nucleoprotein; NTD, N-terminal domain; CTD, C-terminal domain; SD1, subdomain 1; SD2, subdomain 2; S1/S2, S1/S2 cleavage site; S2′, S2′ cleavage site; FP, fusion peptide; HR1, heptad repeat 1; HR2, heptad repeat 2; TM, transmembrane domain; and CT, C-terminal domain. (B) Representative structure of coronavirus S protein. MHV S protein in pre-fusion (S1 and S2 subunits, PDB 3JCL) and post-fusion (S2 subunit, PDB 6B3O) conformations. (C) Representative structures of coronavirus NTD subdomain (BCoV NTD, PDB 4H14) and CTD subdomain (SARS-CoV CTD, PDB 2AJF) with receptor-binding motif (RBM) highlighted in red.

Figure 2.

Coronavirus carbohydrate and protein receptor usage. A phylogenetic analysis of coronavirus spike proteins from representatives of all four genera was performed with corresponding carbohydrate and protein receptors shown along with receptor-binding domains involved. Selected coronavirus spike protein sequences were aligned and a maximum-likelihood (ML) phylogenetic tree was generated. Bootstrap values shown at nodes were calculated from 1000 replicates. The tree is drawn to scale, with branch lengths measured in the number of substitutions per site. Abbreviations used: NTD, N-terminal domain; CTD, C-terminal domain; SA, sialic acid; Neu5Gc, N-glycolylneuraminic acid; Neu5Ac, N-acetylneuraminic acid; CEACAM1, carcinoembryonic antigen-related cell adhesion molecule 1; 9-O-ac., 9-O-acetylated sialic acids; α2,3, α2,3-linked sialic acids; APN, aminopeptidase N; ACE2, angiotensin converting enzyme 2; DPP4, dipeptidyl peptidase 4; HS, heparan sulfate; DC-SIGN, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; L-SIGN, liver/lymph node-specific intracellular adhesion molecules-3 grabbing non-integrin; HE, hemagglutinin esterase; CEACAM5, carcinoembryonic antigen-related cell adhesion molecule 5; GRP78, 78-kDa glucose-regulated protein; NRP1, neuropilin-1; and CD147, basigin.

Figure 3.

Structures of the NTD of members of the Betacoronavirus genus. Displayed are the structures of BCoV NTD (PDB 4H14) known to bind to 9-O-acetylated sialic acids, MHV NTD, which recognizes the proteinaceous receptor mCEACAM1a but conserves structural features of the galectin fold (PDB 3JCL), MERS-CoV NTD (PDB 6Q06), which binds sialosides with a preference for α2,3-linked sialic acids, and SARS-CoV-2 NTD (PDB 6ZGE), which was suggested to bind to α,N-acetyl neuraminic acid (see text for details).

Figure 4.

Co-operative roles of the spike protein NTD and CTD receptor binding modules in coronavirus ecology. Schematic of coronavirus NTD and CTD subdomains with their complementary characteristics and roles in coronavirus tropism and host range.