Coronavirus Proteins as Ion Channels: Current and Potential Research

Abstract

Coronavirus (CoV) outbreaks have recently emerged as a global public health threat due to their exceptional zoonotic potential - a feature arising from their ability to infect a diverse range of potential hosts combined with their high capacity for mutation and recombination. After Severe Acute Respiratory Syndrome (SARS) CoV-1 in 2003 and Middle East Respiratory Syndrome (MERS) CoV in 2012, with the current SARS-CoV-2 pandemic we are now in the midst of the third deadly international CoV outbreak in less than 20 years. Coronavirus outbreaks present a critical threat to global public health and an urgent necessity for therapeutic options. Here, we critically examine the current evidence for ion channel activity in CoV proteins and the potential for modulation as a therapeutic approach.

Keywords: Severe Acute Respiratory Syndrome coronavirus; Severe Acute Respiratory Syndrome coronavirus-2; bilayer; electrophysiology; ion channel; spike protein.

Figure 1

Proposed SARS-Cov E and 8a structures (A) Proposed homopentameric structure of the E protein (32), viewed (left) through the membrane, and (right) on the plane of the membrane. The structural model includes a ~2Å radius constriction, formed by the sidechains of V25 and V28, which could conceivably act as a channel gate, and an extended central “pore” of <6Å in radius (34) [From Surya et al. BBA-Biomembranes 2018 1860: 1309-1317. With publisher’s permission] (B). Proposed pentameric structure of the 8a protein. (left) The single transmembrane domain (TMD) 8a 1–22 is shown at the beginning (0 ns) and end of a 50-ns MD simulation, (right). Top view (left) and side view (right) of a pentameric bundle of 8a 1–22 at the beginning (upper) and end of 50 ns MD simulation (lower). The protein backbones are drawn in blue with the side chains shown as sticks and van der Waals surface representation. Residues Thr-8, Ser-11, and 214 are shown in pink and light red, respectively. All cysteine residues, Cys-9, 213, and 217, are shown in yellow. Phosphorous atoms of the lipids are shown in orange spheres. Lipid and water molecules are omitted for clarity. [Relabeled from Hsu et al., Proteins. 2015; 83: 300–308. With publisher’s permission].

Figure 2

3a Protein topology and sequence alignment among corona viruses (A) 3a protein topology. (B) Multiple sequence alignment of 3a protein from corona viruses. Secondary structures [alpha helices (coils) and beta strands (arrows)] observed in the EM structure by Kern et al. (41) are indicated. Transmembrane regions (gray), novel mutations in CoV-2 (red), TRAF-binding motif (blue), epitopes for natural antibodies against 3A (orange), cysteines involved in dimer formation (magenta), internalization signal (purple), ER trafficking motif (green) and caveolin binding motif (cyan) are shown. Triangles indicate mutations suggested to affect 3a ion channel activity; dots indicate potentially critical residues inferred from the new EM structure.

Figure 3

High-resolution 3a protein structure (A) Model of 3a dimer (left) and dimer-of-dimer (right) proteins embedded in lipid nanodiscs (PDB: 6XDC) (41). (B) (above) Location of charged residues within the cavity. (below) Location of cysteine residues near the dimer-dimer interface. (C) Space-filling model colored to illustrate the isoelectric potential of the dimeric protein (+3 blue and −3 red) computed by PDB2PQR (42) and APBS (43) webservers with default settings.