Chapter 2 Viral Channel-Forming Proteins

Fischer, Wolfgang B.; Krüger, Jens

doi:10.1016/s1937-6448(09)75002-6

Cited by 26 publications

(25 citation statements)

References 172 publications

(202 reference statements)

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“…It is possible that p7 is retained in an inactive state via its interactions with other viral factors, and is later released when it is needed for HCV particle assembly and/or egress. A similar hypothesis has been put forth in the case of the HIV viroporin, Vpu, which can engage in protein-protein interactions, but can also self-assemble to form channels or pores [37]. Because of its central organizing role in HCV assembly, it is tempting to speculate that NS2 is involved in the orchestration of p7 release and assembly [28]– [31].…”

Section: Discussionmentioning

confidence: 71%

“…Compared with selective ion channels of eukaryotic cells like, for instance, voltage-gated potassium channels, which exhibit specific pore-lining motifs [63], the p7 channel appears to have a minimalist channel architecture, as generally observed in viroporins [37]. It is solely held together through non-covalent, inter-monomer interactions, and tends to form a stable pore open to the solvent.…”

Section: Discussionmentioning

confidence: 93%

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The p7 Protein of Hepatitis C Virus Forms Structurally Plastic, Minimalist Ion Channels

et al. 2012

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Hepatitis C virus (HCV) p7 is a membrane-associated oligomeric protein harboring ion channel activity. It is essential for effective assembly and release of infectious HCV particles and an attractive target for antiviral intervention. Yet, the self-assembly and molecular mechanism of p7 ion channelling are currently only partially understood. Using molecular dynamics simulations (aggregate time 1.2 µs), we show that p7 can form stable oligomers of four to seven subunits, with a bias towards six or seven subunits, and suggest that p7 self-assembles in a sequential manner, with tetrameric and pentameric complexes forming as intermediate states leading to the final hexameric or heptameric assembly. We describe a model of a hexameric p7 complex, which forms a transiently-open channel capable of conducting ions in simulation. We investigate the ability of the hexameric model to flexibly rearrange to adapt to the local lipid environment, and demonstrate how this model can be reconciled with low-resolution electron microscopy data. In the light of these results, a view of p7 oligomerization is proposed, wherein hexameric and heptameric complexes may coexist, forming minimalist, yet robust functional ion channels. In the absence of a high-resolution p7 structure, the models presented in this paper can prove valuable as a substitute structure in future studies of p7 function, or in the search for p7-inhibiting drugs.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 93%

The p7 Protein of Hepatitis C Virus Forms Structurally Plastic, Minimalist Ion Channels

et al. 2012

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“…Viral channel forming proteins (Fischer & Sansom 2002; Gonzales & Carrasco 2003; Fischer & Krüger 2009; Nieva et al 2012) are candidate proteins which can be built along these considerations using computational techniques (Krüger & Fischer 2009; Hsu & Fischer 2011). Viral channel forming proteins are found as bitopic and polytopic membrane proteins with up to three TMDs (Hsu & Fischer 2011; Fischer & Krüger 2009; Wang et al 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Viral channel forming proteins are found as bitopic and polytopic membrane proteins with up to three TMDs (Hsu & Fischer 2011; Fischer & Krüger 2009; Wang et al 2010). What they all have in common, is their existence as homo-oligomers with a minimum number of four monomeric units in order to be totally functional.…”

Section: Introductionmentioning

confidence: 99%

Computational modeling of the p7 monomer from HCV and its interaction with small molecule drugs

Wang¹,

Hsu

Fischer³

2013

SpringerPlus

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Hepatitis C virus p7 protein is a 63 amino acid polytopic protein with two transmembrane domains (TMDs) and one of the prime targets for anti HCV drug development. A bio-inspired modeling pathway is used to generate plausible computational models of the two TMDs forming the monomeric protein model. A flexible region between Leu-13 and Gly-15 is identified for TMD11-32 and a region around Gly-46 to Trp-48 for TMD236-58. Mutations of the tyrosine residues in TMD236-58 into phenylalanine and serine are simulated to identify their role in shaping TMD2. Lowest energy structures of the two TMDs connected with the loop residues are used for a posing study in which small molecule drugs BIT225, amantadine, rimantadine and NN-DNJ, are identified to bind to the loop region. BIT225 is identified to interact with the backbone of the functionally important residues Arg-35 and Trp-36.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-2-324) contains supplementary material, which is available to authorized users.

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“…Although its detailed mechanism remains largely unknown, this effect on the plasma membrane could be due to the expression of many virusencoded proteins [3][4][5]. The expression of protein 2B from polioviruses and coxsackieviruses can increase the permeability of the cell membrane to the translational inhibitor hygromycin B [6,7].…”

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confidence: 99%

DIDS blocks a chloride-dependent current that is mediated by the 2B protein of enterovirus 71

Xie

Wang

et al. 2011

Cell Res

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Enterovirus 71 (EV71), which belongs to the genus Enterovirus of the family Picornaviridae, is one of the major pathogens that cause hand, foot and mouth disease, primarily in infants and young children. In recent years, epidemic and sporadic outbreaks of neurovirulent EV71 infections have been reported in many countries and regions, including Japan, China and Taiwan [1]. However, there is still no effective antiviral treatment against severe EV71 infections, and no vaccine is available.During their life cycle, viruses can induce many changes in their host cells including increased plasma membrane permeability [2]. Although its detailed mechanism remains largely unknown, this effect on the plasma membrane could be due to the expression of many virusencoded proteins [3][4][5]. The expression of protein 2B from polioviruses and coxsackieviruses can increase the permeability of the cell membrane to the translational inhibitor hygromycin B [6,7]. A recent study that focused on protein 2B from coxsackievirus B3 (CVB3) showed that 2B can facilitate virus release by increasing the concentration of free cytosolic Ca 2+ [8]. However, little is known about 2B proteins from other enteroviruses, and the detailed mechanisms of how 2B changes cellular ion homeostasis and, thus, promotes virion release remain unclear.Because the 2B protein of CVB3 can form homodimers and homotetramers that are located primarily in the cell membrane system, including the Golgi complex [9, 10], we asked whether the 2B proteins of EV71 might share similar characteristics. To address this question, the sequences of the 2B genes from these two viruses were compared. These sequences have relatively high similarity, especially within their two transmembrane domains (TM1 and TM2), structures that are essential for the function of viroporins (Supplementary information, Figure S1A). Next, we examined the subcellular localization of the EV71 2B protein in human rhabdomyosarcoma (RD) cells and found that it colocalized with the Golgi complex (Supplementary information, Figure S1B).

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Chapter 2 Viral Channel-Forming Proteins

Cited by 26 publications

References 172 publications

The p7 Protein of Hepatitis C Virus Forms Structurally Plastic, Minimalist Ion Channels

The p7 Protein of Hepatitis C Virus Forms Structurally Plastic, Minimalist Ion Channels

Computational modeling of the p7 monomer from HCV and its interaction with small molecule drugs

DIDS blocks a chloride-dependent current that is mediated by the 2B protein of enterovirus 71

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