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1.A.68 The Viral Small Hydrophobic Viroporin (V-SH) Family

The small hydrophobic (SH) protein from the human respiratory syncytial virus (hRSV) is a glycoprotein of 64 amino acids with one putative TMS and channel activity. Although SH proteins are important for viral infectivity, their exact roles during viral infection are not clear. Gan et al., 2008 studied the secondary structure, orientation, and oligomerization of the transmembrane domain of SH (SH-TM) in the presence of lipid bilayers. Only one oligomer, a pentamer, was observed. 

Conductance studies of SH-TM demonstrated ion channel activity which is cation selective and inactive below the predicted pK(a) of histidine. Thus, the transmembrane domain of the SH protein forms pentameric alpha-helical bundles that form cation-selective ion channels in planar lipid bilayers. Gan et al., 2008 suggest a model for this pore.

The absence of the small hydrophobic (SH) protein encoded by the human respiratory syncytial virus (hRSV) leads to viral attenuation and prevents apoptosis in infected cells. Gan et al. (2012) examined the structure of the SH protein in detergent micelles and in lipid bilayers. In detergent micelles, the TM domain is flanked N-terminally by a α-helix that forms a ring around the lumen of the pore, and C-terminally by an extended β-turn. The SH protein was found in the plasma membrane of transiently expressing HEK293 cells, which showed pH-dependent (acid-activated) channel activity. Channel activity was abolished in mutants lacking both native His residues, H22 and H51, but not when either His was present. Gan et al. (2012) proposed that the pentameric SH protein is a physiologically relevant conformation, albeit probably not the only one, in which SH contributes to RSV infection and replication.

The generalized reaction catalyzed by V-SHP is:

ions (in) ⇌ ions (out)

References associated with 1.A.68 family:

Araujo, G.C., R.H. Silva, L.P. Scott, A.S. Araujo, F.P. Souza, and R.J. de Oliveira. (2016). Structure and functional dynamics characterization of the ion channel of the human respiratory syncytial virus (hRSV) small hydrophobic protein (SH) transmembrane domain by combining molecular dynamics with excited normal modes. J Mol Model 22: 286. 27817112
Gan SW., Tan E., Lin X., Yu D., Wang J., Tan GM., Vararattanavech A., Yeo CY., Soon CH., Soong TW., Pervushin K. and Torres J. (2012). The small hydrophobic protein of the human respiratory syncytial virus forms pentameric ion channels. J Biol Chem. 287(29):24671-89. 22621926
Gan, S.W., L. Ng, X. Lin, X. Gong, and J. Torres. (2008). Structure and ion channel activity of the human respiratory syncytial virus (hRSV) small hydrophobic protein transmembrane domain. Protein. Sci. 17: 813-820. 18369195
Hyser, J.M. and M.K. Estes. (2015). Pathophysiological Consequences of Calcium-Conducting Viroporins. Annu Rev Virol 2: 473-496. 26958925
Karger, A., U. Schmidt, and U.J. Buchholz. (2001). Recombinant bovine respiratory syncytial virus with deletions of the G or SH genes: G and F proteins bind heparin. J Gen Virol 82: 631-640. 11172105
Li, Y., J. To, C. Verdià-Baguena, S. Dossena, W. Surya, M. Huang, M. Paulmichl, D.X. Liu, V.M. Aguilella, and J. Torres. (2014). Inhibition of the human respiratory syncytial virus small hydrophobic protein and structural variations in a bicelle environment. J. Virol. 88: 11899-11914. 25100835
Russell, R.F., J.U. McDonald, M. Ivanova, Z. Zhong, A. Bukreyev, and J.S. Tregoning. (2015). Partial Attenuation of Respiratory Syncytial Virus with a Deletion of a Small Hydrophobic Gene Is Associated with Elevated Interleukin-1β Responses. J. Virol. 89: 8974-8981. 26085154
Sancho, D., O.P. Joffre, A.M. Keller, N.C. Rogers, D. Martínez, P. Hernanz-Falcón, I. Rosewell, and C. Reis e Sousa. (2009). Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458: 899-903. 19219027
Surya, W. and J. Torres. (2015). Sedimentation Equilibrium of a Small Oligomer-forming Membrane Protein: Effect of Histidine Protonation on Pentameric Stability. J Vis Exp. 25867485