Viral Membrane Channels: Role and Function in the Virus Life Cycle

Sze, Ching Wooen; Tan, Yee-Joo

protein 4 (NSP4) of rotavirus [49] and 3a of severe acute respiratory syndrome SARS-CoV [31]. Due to their high structural variability under different conditions, solving the architecture of viroporins under physiological environment has been difficult. However, recent advancement in technology such as the ability to characterize protein structure at the atomic resolution using nuclear magnetic resonance (NMR) spectroscopy, has successfully resolved the structure of several viroporins [50] [51] [52] [53] . For example, the M2 of IAV forms a tetrameric pore on the plasma membrane that adopts different conformations as it conducts proton across the membrane [54] [55] [56] , whereas for p7 of HCV, a hexameric flower-shaped complex was revealed via single-particle electron microscopy [57, 58] . p7 has also been found to exist in heptameric form using transmission electron microscopy [59] and a model of how both forms could coexist was proposed [60] . Several key residues that line the inside of the ion channel have been shown to be essential for the activation of the protein via protonation. For instance, mutating the two key histidine residues, H22 and H51 of the human respiratory syncytial virus (hRSV), SH viroporin rendered the ion channel inactive [61] , which is reminiscent of the H37 residue in the M2 ion channel [62] . Viroporins have several known functions at different stages of the viral replication depending on their cellular location during the viral life cycle. While the majority of viroporins play a major role in the final viral release and budding stages, some have been proven to be essential at the early viral genome uncoating and replication steps. Table 1 gives a list of viroporins and their known roles during viral replication determined thus far. Viroporin does not form part of the viral RNA replication complex but is absolutely necessary for the pathogenesis. For instance, the absence of the Vpu viroporin in HIV-1 Figure 1 . Classification of viroporins based on their membrane topology. Class I and Class II viroporins have one and two TMD, respectively. Class IA viroporins have their N-termini facing the ER lumen while Class IB have their C-termini in the cytosolic side. Class IIA viroporins have both the N-and C-termini in the lumenal side while Class IIB have them facing the cytosol. A putative Class III viroporin with three TMDs is depicted in this figure, following the proposal of viroporins with three TMDs. Figure adapted from [2] .