Membrane binding proteins of coronaviruses

J Alsaadi, Entedar A; Jones, Ian M

The fusion process between viral and host membranes, mediated in CoVs by the S protein, is a crucial step in enveloped virus infection [15, 16] . The S protein is a large class I fusion protein responsible for virus binding to target cells via cell surface receptors, which for CoVs can range from simple sugars to complex proteins (reviewed in [17, 18] ). For example the entry receptor for MERS-CoV infection has been identified as dipeptidyl peptidase-4 (DPP4) found on a variety of cell types including epithelial cells of the respiratory tract [19] . As a result, receptor distribution and the CoV-S-receptor interaction often defines tissue tropism and host range [18, 19] . The S protein consists of two subunits, S1 and S2, with S1 at the N-terminus providing the receptor binding function and S2 at the C-terminus providing fusion activity [15] . The subunits are cleaved from the complete S by host cell proteases including members of the cathepsin family and transmembrane protease serine 2 (TMPRSS2) [20] . Following receptor binding by S1 and uptake into a vesicle the fusion mechanism of S2 acts to bring the viral and cellular membranes into such close proximity that fusion occurs [21, 22] . The S2 sequence contains conserved regions that are necessary for function, notably a fusion peptide and two conserved heptad repeats (HR) [18] . Briefly, significant conformational change occurs in the late clathrin-coated endocytosed vesicle leading to release of the fusion peptide to interact with the vesicle membrane, provided that S has been cleaved into its requisite subdomains [23] . The collapse of S2, which is now bridging the virus and cellular membranes, pulls the two membranes together with HR1 and HR2 forming the canonical 6-helix bundle first described for CoVs in mouse hepatitis virus (MHV) [24] .