Pentameric viral ion channels: From structure to function

Abstract

A family of small polypeptides in many virus types associate to form oligomers and have channel activity. These proteins have been referred to as viroporins or virochannels and are increasingly recognized as important virulence factors and potential drug targets. In this review, we focus on two of the viroporins that have been studied in more detail from a structural and functional point of view. One is the 76-residue envelope (E) protein found in coronaviruses (CoVs) that causes the severe acute respiratory syndrome (SARS). The other is the 65-residue small hydrophobic (SH) protein found in a paramyxovirus, the respiratory syncytial virus (RSV). RSV SH and SARS-CoV E proteins are short polypeptides with a single transmembrane domain. In both cases, the presence of the viroporin has a protective effect on cells, preventing early apoptosis, but it leads to increased virulence in infected animal models. Both viroporins form homopentameric oligomers that show channel activity with no or low selectivity. The role of channel activity is still unclear, but associations have been made to facilitation of the egress of the virus by modification of the secretory pathway, and contributions to inflammation. SARS-CoV E protein has a cytoplasmically oriented C-terminus and a lumenal N-terminus, whereas the opposite orientation is found in RSV SH protein. Despite this opposite topology, nuclear magnetic resonance (NMR)-based structural models of these two channels show a similar champagne flute shape, with the wider opening facing the cytoplasmic side. Good channel inhibitors are lacking, but those found seem to have a preference for the narrow end of the channel. Availability of good inhibitors will help reveal the specific role of these channels in the life cycle of these viruses.