Mechanisms of coronavirus cell entry mediated by the viral spike protein

Abstract

Coronaviruses are enveloped positive-stranded RNA viruses that replicate in the cytoplasm. To deliver their nucleocapsid into the host cell, they rely on the fusion of their envelope with the host cell membrane. The spike glycoprotein (S) mediates virus entry and is a primary determinant of cell tropism and pathogenesis. It is classified as a class I fusion protein, and is responsible for binding to the receptor on the host cell as well as mediating the fusion of host and viral membranes-A process driven by major conformational changes of the S protein. This review discusses coronavirus entry mechanisms focusing on the different triggers used by coronaviruses to initiate the conformational change of the S protein: receptor binding, low pH exposure and proteolytic activation. We also highlight commonalities between coronavirus S proteins and other class I viral fusion proteins, as well as distinctive features that confer distinct tropism, pathogenicity and host interspecies transmission characteristics to coronaviruses.

Keywords: coronavirus; fusion; proteolytic activation; spike; viral entry.

Figure 1

Coronavirus genomes (A). The genome of four different coronaviruses is depicted. The open reading frame (ORF)1a/b is colored in red. The HE gene present in MHV-A59 is represented in purple. The gene of structural proteins S (blue), E (pink), M (dark pink) and N (cyan) are localized in the 3' part of the genome. ORFs encoding accessory proteins are represented in grey. Coronavirus virion structure (B).

Figure 2

Severe acute respiratory syndrome (SARS)-CoV spike protein schematic. The spike protein ectodomain consists of the S1 and S2 domains. The S1 domain contains the receptor binding domain and is responsible for recognition and binding to the host cell receptor. The S2 domain, responsible for fusion, contains the putative fusion peptide (blue) and the heptad repeat HR1 (orange) and HR2 (brown). The transmembrane domain is represented in purple. Cleavage sites are indicated with arrows.

Figure 3

SARS-CoV spike protein three-dimensional predicted structure. This representation, shows the trimeric (inset) and monomeric forms of the protein and is based on the three-dimensional predicted model found in the PDB database (PDB entry 1T7G, [109]). Note that the predicted model does not include residues 681-736 of the protein. The S1 and S2 domains as well as the cleavage sites and putative fusion peptide are highlighted.