The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, Amantadine

Griffin, Stephen; Beales, Lucy; Clarke, Dean; Worsfold, O.; Evans, Stephen D.; Jaeger, Joachim; Harris, Mark; Rowlands, David J.

doi:10.1016/s0014-5793(02)03851-6

Cited by 422 publications

(458 citation statements)

References 30 publications

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“…The nature of the residues, particularly those with short side chains (Gly, Ala, Pro), that are present within identical grooves in TM2 and TM4 suggests that the corresponding helical faces might be involved in specific helix-helix interactions with a common partner, either p13 itself or another viral or cellular protein that is essential for virus replication. Three recent publications suggest that the HCV p7 protein may function as an ion channel (12)(13)(14). For it to have such activity, HCV p7 would need to multimerize, and p7 was indeed observed to form putative hexameric ring structures in membranes (12).…”

Section: Discussionmentioning

confidence: 99%

“…Three recent publications suggest that the HCV p7 protein may function as an ion channel (12)(13)(14). For it to have such activity, HCV p7 would need to multimerize, and p7 was indeed observed to form putative hexameric ring structures in membranes (12). By analogy with the p7 protein, p13 oligomerization might occur through intra-and/or intermolecular interactions involving the clearly homologous grooves in the TM2 and TM4 domains.…”

Section: Discussionmentioning

confidence: 99%

“…A small protein of 7 kDa, p7, has been identified in the HCV polyprotein between the E2 glycoprotein and the first nonstructural protein, NS2 (10). Recently, p7 has been suggested to be a membrane-spanning protein localized to the endoplasmic reticulum (11) and to function as an ion channel (12)(13)(14). Pestiviruses (e.g.…”

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confidence: 99%

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Characterization of GB Virus B Polyprotein Processing Reveals the Existence of a Novel 13-kDa Protein with Partial Homology to Hepatitis C Virus p7 Protein

Ghibaudo

Cohen

Pénin

et al. 2004

Journal of Biological Chemistry

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Although responsible for a major health problem worldwide, hepatitis C virus is difficult to study because of the absence of fully permissive cell cultures or experimental animal models other than the chimpanzee. GB virus B (GBV-B), a closely related hepatotropic virus that infects small New World primates and replicates efficiently in primary hepatocyte cultures, is an attractive surrogate model system. However, little is known about processing of the GBV-B polyprotein. Because an understanding of these events is critical to further development of model GBV-B systems, we characterized signal peptidase processing of the polyprotein segment containing the putative structural proteins. We identified the exact N termini of the mature GBV-B envelope proteins, E1 and E2, and the first nonstructural protein, NS2, by direct amino acid sequencing. Interestingly, these studies document the existence of a previously unrecognized 13-kDa protein (p13) located between E2 and NS2 within the polyprotein. We compared the sequence of the p13 protein to that of hepatitis C virus p7, a small membrane-spanning protein with a similar location in the polyprotein and recently identified ion channel activity. The C-terminal half of p13 shows clear homology with p7, suggesting a common function, but the substantially larger size of p13, with 4 rather than 2 predicted transmembrane segments, indicates a different structural organization and/or additional functions. The identification of p13 in the GBV-B polyprotein provides strong support for the hypothesis that ion channel-forming proteins are essential for the life cycle of flaviviruses, possibly playing a role in virion morphogenesis and/or virus entry into cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Characterization of GB Virus B Polyprotein Processing Reveals the Existence of a Novel 13-kDa Protein with Partial Homology to Hepatitis C Virus p7 Protein

Ghibaudo

Cohen

Pénin

et al. 2004

Journal of Biological Chemistry

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“…The amino-terminal one-third of the polyprotein encodes the virion structural proteins: the highly basic core (C) protein, and glycoproteins E1 and E2. After the structural region comes a small integral membrane protein, p7, which seems to function as an ion channel 18,19 . The remainder of the genome encodes the nonstructural (NS) proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B, which coordinate the intracellular processes of the virus life cycle.…”

Section: Initial Studies: Hcv Translation and Polyprotein Processingmentioning

confidence: 99%

Unravelling hepatitis C virus replication from genome to function

Lindenbach

Rice

2005

Nature

751

561

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Since the discovery of the hepatitis C virus over 15 years ago, scientists have raced to develop diagnostics, study the virus and find new therapies. Yet virtually every attempt to dissect this pathogen has met with roadblocks that impeded progress. Its replication was restricted to humans or experimentally infected chimpanzees, and efficient growth of the virus in cell culture failed until very recently. Nevertheless hard-fought progress has been made and the first wave of antiviral drugs is entering clinical trials.virus life cycle: first, as a messenger RNA (mRNA) for translation of the viral proteins; second as a template for RNA replication; and third, as a nascent genome packaged within new virus particles. Virions presumably form by budding into the endoplasmic reticulum (ER) and leave the cell through the secretory pathway.Researchers have followed each aspect of the virus life cycle in turn. Just as infection starts from an HCV genome entering the cytoplasm and progressing through translation, replication and particle production, our understanding has progressed from having a genome sequence to understanding translation and the viral gene products, characterizing RNA replication, and establishing systems to characterize virus particles and infectivity. In this review, we summarize the current understanding of HCV replication with special emphasis on recent developments. As space is limited, we cannot be comprehensive; readers may wish to consult other reviews for detail and breadth 5,13,14. Initial studies: HCV translation and polyprotein processingThe identification of HCV yielded a partial viral genome sequence 5 . Research in the early 1990s focused on dissecting HCV gene expression and characterizing the gene products. Much has been learned about the biochemistry of three key enzymes, and structural information is now available at the atomic level for roughly half of the proteincoding region.Translation of the HCV genome, which lacks a 5፱ cap, depends on an internal ribosome entry site (IRES) within the 5፱-noncoding region (NCR). The HCV IRES binds 40S ribosomal subunits directly and avidly, bypassing the need for pre-initiation factors, and inducing an mRNA-bound conformation in the 40S subunit 15 . The IRES-40S complex then recruits eukaryotic initiation factor (eIF) 3 and the ternary complex of Met-tRNA-eIF2-GTP to form a non-canonical 48S intermediate, before a kinetically slow transition to the translationally active 80S complex 16,17 .Once initiated, translation of the HCV genome produces a large polyprotein that is proteolytically cleaved to produce 10 viral proteins (Fig. 2a). The amino-terminal one-third of the polyprotein encodes the virion structural proteins: the highly basic core (C) protein, and glycoproteins E1 and E2. After the structural region comes a small integral membrane protein, p7, which seems to function as an ion channel 18,19 . The remainder of the genome encodes the nonstructural (NS) proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B, which coordinate the intracellular process...

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“…p7 forms a hexameric cation channel whose activity is also inhibited by amantadine. [40][41][42] Although, like p13 II , p7 is mainly localized to HTLV-1 p13 II and mitochondria DM D'Agostino et al mitochondria, 41 its effects on mitochondrial morphology and function have not been investigated. Another small viral protein with channel forming-properties is human immunodeficiency virus type 1 Vpr, a 96-amino acid, multifunctional protein that is detected in mature viral particles, the nucleus, and mitochondria.…”

Section: Effects Of P13 II On Mitochondrial Morphologymentioning

confidence: 99%

The human T-cell leukemia virus type 1 p13II protein: effects on mitochondrial function and cell growth

D’Agostino

Silic-Benussi

Hiraragi³

et al. 2005

Cell Death Differ

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Abstractp13 II of human T-cell leukemia virus type 1 (HTLV-1) is an 87-amino-acid protein that is targeted to the inner mitochondrial membrane. p13 II alters mitochondrial membrane permeability, producing a rapid, membrane potential-dependent influx of K þ . These changes result in increased mitochondrial matrix volume and fragmentation and may lead to depolarization and alterations in mitochondrial Ca 2 þ uptake/retention capacity. At the cellular level, p13 II has been found to interfere with cell proliferation and transformation and to promote apoptosis induced by ceramide and Fas ligand. Assays carried out in T cells (the major targets of HTLV-1 infection in vivo) demonstrate that p13 II -mediated sensitization to Fas ligand-induced apoptosis can be blocked by an inhibitor of Ras farnesylation, thus implicating Ras signaling as a downstream target of p13 II function. Cell Death and Differentiation (2005) 12, 905-915.

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The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, Amantadine

Cited by 422 publications

References 30 publications

Characterization of GB Virus B Polyprotein Processing Reveals the Existence of a Novel 13-kDa Protein with Partial Homology to Hepatitis C Virus p7 Protein

Characterization of GB Virus B Polyprotein Processing Reveals the Existence of a Novel 13-kDa Protein with Partial Homology to Hepatitis C Virus p7 Protein

Unravelling hepatitis C virus replication from genome to function

The human T-cell leukemia virus type 1 p13II protein: effects on mitochondrial function and cell growth

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