Membrane binding proteins of coronaviruses

Abstract

Coronaviruses (CoVs) infect many species causing a variety of diseases with a range of severities. Their members include zoonotic viruses with pandemic potential where therapeutic options are currently limited. Despite this diversity CoVs share some common features including the production, in infected cells, of elaborate membrane structures. Membranes represent both an obstacle and aid to CoV replication - and in consequence - virus-encoded structural and nonstructural proteins have membrane-binding properties. The structural proteins encounter cellular membranes at both entry and exit of the virus while the nonstructural proteins reorganize cellular membranes to benefit virus replication. Here, the role of each protein in membrane binding is described to provide a comprehensive picture of their role in the CoV replication cycle.

Keywords: bending; coronavirus; egress; fusion; membrane; peptide; replication; web.

Figure 1.. Schematic representation of a coronavirus particle.

The structural components of the virus are indicated. Small amounts of host cell and virus nonstructural proteins, presumed to be captured nonspecifically during the budding process, are also found in virions but are not illustrated.

Figure 2.. The coronavirus replication cycle highlighting areas where membrane interaction occurs.

(1) Most Coronaviruseses enter by receptor mediated endocytosis. The positive sense genomic RNA is released into the cytoplasm and translated into the initial virus polyproteins which encode the nsp. (2) The nsp stimulate the production of DMVs and establish the replication transcription complexes (RTC), which produce the -ve strand replicative intermediate from which more +ve strand genomes and mRNAs are produced. Translation of the N mRNA produces the N protein in the cytoplasm which combines with the new genomes to form RNPs while translation of the remaining structural proteins, M, E and S occurs in the ER where they accumulate in the ERGIC and cis-Golgi. (3) Virus assembly begins and completes as the protein cargos migrate through the Golgi stacks resulting in new virus particles in vesicles (4), which eventually fuse with the plasma membrane. DMV: Double-membrane vesicle; ER: Endoplasmic reticulum; ERGIC: Endoplasmic reticulum Golgi intermediate compartment; nsp: Nonstructural protein; RTC: Replication transcription complex.

Figure 3.. The suggested topology for the coronavirus nonstructural proteins associated with membrane deformation.

Three proteins, nsp 3, 4 and 6 are implicated in membrane curvature and the formation of subcellular membrane organelles. The topologies suggested within the lipid bilayer (red) are supported by experimental evidence but may not be the same for all Coronaviruseses. In all cases the white cylinders represent hydrophobic stretches of amino acids that are consistent with transmembrane domains although all may not be used as such (see nsp6). Only the region of the protein that interacts with the membrane is shown. N- the amino terminus of the protein, C- the carboxyl terminus of the protein, CHO- the addition of carbohydrate. The cartoon is not to scale. Nsp: Nonstructural protein.