Direct visualization of the small hydrophobic protein of human respiratory syncytial virus reveals the structural basis for membrane permeability

Carter, Stephen D.; Dent, Kyle; Atkins, Elizabeth; Foster, Toshana L.; Verow, Mark; Gorny, Petra; Harris, Mark; Hiscox, Julian A.; Ranson, Neil A.; Griffin, Stephen; Barr, John N.

doi:10.1016/j.febslet.2010.05.006

Cited by 61 publications

(58 citation statements)

References 19 publications

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“…Thus, whilst clearly an indirect measure of channel activity, such indirect assays conducted upon multiple channels [e.g. IAV M2, HCV p7, classical swine fever virus (CSFV) p7, HPV E5, respiratory syncytial virus (RSV) SH and picornavirus 2B] have provided important insights into their activity as well as their inhibition by small molecules, with results generally consistent with those observed in culture (Agirre et al, 2002;Aldabe et al, 1996;Atkins et al, 2014;Carter et al, 2010;Gladue et al, 2012;Guinea & Carrasco, 1994;Lama & Carrasco, 1992;Perez et al, 1997;Sanz et al, 1994;StGelais et al, 2007;Wetherill et al, 2012;Wozniak et al, 2010).…”

Section: General Viroporin Characteristicssupporting

confidence: 49%

“…Solution NMR structures have been reported for the pentameric bundles, yet have not been added to the PDB (Gan et al, 2008(Gan et al, , 2012. Both SH TMD peptides and full-length protein form cation-selective channels in vitro (Gan et al, 2008), as well as promoting bacterial membrane permeability (Perez et al, 1997) and mediating dye release from liposomes (Carter et al, 2010). The effect of low pH upon channel opening appears to be context dependent, with conserved His22, His51 and Trp15 residues implicated in channel gating/opening.…”

Section: Other Rna Virus Viroporinsmentioning

confidence: 99%

“…SH is commonly thought to form pentameric oligomers (Collins & Mottet, 1993;Gan et al, 2008Gan et al, , 2012, although hexamers have also been reported (Carter et al, 2010). Solution NMR structures have been reported for the pentameric bundles, yet have not been added to the PDB (Gan et al, 2008(Gan et al, , 2012.…”

Section: Other Rna Virus Viroporinsmentioning

confidence: 99%

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Viroporins: structure, function and potential as antiviral targets

Scott

Griffin

2015

Journal of General Virology

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120

146

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The channel-forming activity of a family of small, hydrophobic integral membrane proteins termed 'viroporins' is essential to the life cycles of an increasingly diverse range of RNA and DNA viruses, generating significant interest in targeting these proteins for antiviral development. Viroporins vary greatly in terms of their atomic structure and can perform multiple functions during the virus life cycle, including those distinct from their role as oligomeric membrane channels. Recent progress has seen an explosion in both the identification and understanding of many such proteins encoded by highly significant pathogens, yet the prototypic M2 proton channel of influenza A virus remains the only example of a viroporin with provenance as an antiviral drug target. This review attempts to summarize our current understanding of the channel-forming functions for key members of this growing family, including recent progress in structural studies and drug discovery research, as well as novel insights into the life cycles of many viruses revealed by a requirement for viroporin activity. Ultimately, given the successes of drugs targeting ion channels in other areas of medicine, unlocking the therapeutic potential of viroporins represents a valuable goal for many of the most significant viral challenges to human and animal health.

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Section: General Viroporin Characteristicssupporting

confidence: 49%

Section: Other Rna Virus Viroporinsmentioning

confidence: 99%

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Viroporins: structure, function and potential as antiviral targets

Scott

Griffin

2015

Journal of General Virology

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120

146

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“…Therefore, the above studies point unequivocally to a pentameric form for SH. Recent electron microscopy studies using a >80 residue long construct containing SH protein have produced ambiguous results that could be assigned to a pentamer or a hexamer (Carter et al, 2010).…”

Section: Oligomerization Of Sh Proteinmentioning

confidence: 99%

Structural and Functional Aspects of the Small Hydrophobic (SH) Protein in the Human Respiratory Syncytial Virus

Gan¹,

Torres²

2011

Human Respiratory Syncytial Virus Infection

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“…The RSV SH protein is able to alter membrane permeability in bacteria (24) and functions as a cation-selective ion channel in artificial membranes (25), and recent work indicates it has lowpH-activated ion channel activity (26). Fitting with other viroporins, RSV SH can oligomerize as a pentamer (25,27,28) and/or a hexamer (29).…”

mentioning

confidence: 99%

The Human Metapneumovirus Small Hydrophobic Protein Has Properties Consistent with Those of a Viroporin and Can Modulate Viral Fusogenic Activity

Masante

Najjar

Chang

et al. 2014

J Virol

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Human metapneumovirus (HMPV) encodes three glycoproteins: the glycoprotein, which plays a role in glycosaminoglycan binding, the fusion (F) protein, which is necessary and sufficient for both viral binding to the target cell and fusion between the cellular plasma membrane and the viral membrane, and the small hydrophobic (SH) protein, whose function is unclear. The SH protein of the closely related respiratory syncytial virus has been suggested to function as a viroporin, as it forms oligomeric structures consistent with a pore and alters membrane permeability. Our analysis indicates that both the full-length HMPV SH protein and the isolated SH protein transmembrane domain can associate into higher-order oligomers. In addition, HMPV SH expression resulted in increases in permeability to hygromycin B and alteration of subcellular localization of a fluorescent dye, indicating that SH affects membrane permeability. These results suggest that the HMPV SH protein has several characteristics consistent with a putative viroporin. Interestingly, we also report that expression of the HMPV SH protein can significantly decrease HMPV F protein-promoted membrane fusion activity, with the SH extracellular domain and transmembrane domain playing a key role in this inhibition. These results suggest that the HMPV SH protein could regulate both membrane permeability and fusion protein function during viral infection. IMPORTANCE Human metapneumovirus (HMPV), first identified in 2001, is a causative agent of severe respiratory tract disease worldwide. The small hydrophobic (SH) protein is one of three glycoproteins encoded by all strains of HMPV, but the function of the HMPV SH protein is unknown. We have determined that the HMPV SH protein can alter the permeability of cellular membranes, suggesting that HMPV SH is a member of a class of proteins termed viroporins, which modulate membrane permeability to facilitate critical steps in a viral life cycle. We also demonstrated that HMPV SH can inhibit the membrane fusion function of the HMPV fusion protein. This work suggests that the HMPV SH protein has several functions, though the steps in the HMPV life cycle impacted by these functions remain to be clarified. Human metapneumovirus (HMPV) is an enveloped virus belonging to the Pneumovirinae genus of the Paramyxoviridae family. HMPV is associated worldwide with severe respiratory disease, including bronchiolitis and pneumonia (1). Respiratory tract infections caused by HMPV are an important cause of hospitalizations for children under the age of five, with an annual rate of hospitalization similar to that of influenza (2). HMPV is also an important cause of severe respiratory illness in the elderly (3, 4). Studies indicate that the majority of individuals over the age of five are seropositive for HMPV (1, 5). HMPV was identified in 2001 from samples of patients with respiratory syncytial virus (RSV)-like symptoms, as symptoms of HMPV closely resemble those of RSV (5).HMPV, like other paramyxoviruses, encodes two surface glyc...

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Direct visualization of the small hydrophobic protein of human respiratory syncytial virus reveals the structural basis for membrane permeability

Cited by 61 publications

References 19 publications

Viroporins: structure, function and potential as antiviral targets

Viroporins: structure, function and potential as antiviral targets

Structural and Functional Aspects of the Small Hydrophobic (SH) Protein in the Human Respiratory Syncytial Virus

The Human Metapneumovirus Small Hydrophobic Protein Has Properties Consistent with Those of a Viroporin and Can Modulate Viral Fusogenic Activity

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