Virus membrane fusion

Weissenhorn, Winfríed; Hinz, Andreas; Gaudin, Yves

doi:10.1016/j.febslet.2007.01.093

Cited by 195 publications

(213 citation statements)

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“…The fusogenic ability of VSV G has been of significant interest, because, unlike the proposed "spring-loaded" and essentially irreversible metastable state for the pre-fusion state of other fusion proteins such as influenza HA strain X-31 (10), VSV G is apparently fully reversible for fusion activation; it exists in a dynamic equilibrium between the pre-fusion and post-fusion states (11). In addition, whereas most viral fusion proteins can be categorized into an obvious structural group, either class I or class II (12,13), the distinct structural features of VSV G (14,15) have resulted in it being considered a novel "class III" fusion protein (16).…”

mentioning

confidence: 99%

Molecular Architecture of the Bipartite Fusion Loops of Vesicular Stomatitis Virus Glycoprotein G, a Class III Viral Fusion Protein

Sun

Belouzard

Whittaker

2008

Journal of Biological Chemistry

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The glycoprotein of vesicular stomatitis virus (VSV G) mediates fusion of the viral envelope with the host cell, with the conformational changes that mediate VSV G fusion activation occurring in a reversible, low pH-dependent manner. Based on its novel structure, VSV G has been classified as class III viral fusion protein, having a predicted bipartite fusion domain comprising residues Trp-72, Tyr-73, Tyr-116, and Ala-117 that interacts with the host cell membrane to initiate the fusion reaction. Here, we carried out a systematic mutagenesis study of the predicted VSV G fusion loops, to investigate the functional role of the fusion domain. Using assays of low pH-induced cell-cell fusion and infection studies of mutant VSV G incorporated into viral particles, we show a fundamental role for the bipartite fusion domain. We show that Trp-72 is a critical residue for VSV G-mediated membrane fusion. Trp-72 could only tolerate mutation to a phenylalanine residue, which allowed only limited fusion. Tyr-73 and Tyr-116 could be mutated to other aromatic residues without major effect but could not tolerate any other substitution. Ala-117 was a less critical residue, with only charged residues unable to allow fusion activation. These data represent a functional analysis of predicted bipartite fusion loops of VSV G, a founder member of the class III family of viral fusion proteins. Vesicular stomatitis virus (VSV)2 is a prototypic virus in the Rhabdoviridae, which includes many important human, animal, and plant pathogens, including Rabies virus (1). VSV is an enveloped virus that is well known to infect cells via a low pHdependent fusion reaction within endosomes (2-4). The virus contains a single envelope protein, termed the glycoprotein (G), which mediates both attachment to host cells and fusion between the virus envelope and the host cell membrane. This fusion event delivers the VSV genome into the host cell for viral replication. In addition to being a critical determinant of viral pathogenesis, VSV G has also served as an important model for protein folding and transport through the secretory pathway of cells (5). VSV G is used extensively in pseudotyped virus systems and as a delivery system for gene therapy applications (6), and, due to the fact that VSV preferentially replicates and destroys immortalized or tumorigenic cells, the virus has been of great interest as an oncolytic agent in anticancer treatment (7).The mature VSV G protein is an ϳ65-kDa type I transmembrane protein containing 511 amino acids that oligomerizes into a homotrimer during transport to the cell surface, where the trimer is then assembled into the viral particle (8). Unlike many other viral glycoproteins (9), VSV G is not subject to proteolytic priming for fusion activation. The fusogenic ability of VSV G has been of significant interest, because, unlike the proposed "spring-loaded" and essentially irreversible metastable state for the pre-fusion state of other fusion proteins such as influenza HA strain X-31 (10), VSV G is apparently fully re...

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mentioning

confidence: 99%

Molecular Architecture of the Bipartite Fusion Loops of Vesicular Stomatitis Virus Glycoprotein G, a Class III Viral Fusion Protein

Sun

Belouzard

Whittaker

2008

Journal of Biological Chemistry

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“…Rather unexpectedly, we demonstrate that efficient paramyxovirus F-protein-mediated viral entry can proceed independent of complete 6HB assembly. It was suggested that, after activation of paramyxovirus Fprotein refolding and insertion of the fusion peptide into the target membrane, hairpin formation and the assembly of the 6HB fusion core structure pull the viral and target membranes together (1,41,42). This model applies the energy released through formation of the thermodynamically stable fusion core directly to local membrane bending, and the fusion peptides and transmembrane domains function merely as anchor points that are required to transmit elastic stress into the membranes.…”

Section: Discussionmentioning

confidence: 99%

Efficient replication of a paramyxovirus independent of full zippering of the fusion protein six-helix bundle domain

Brindley¹,

Plattet²,

Plemper³

2014

Proc. Natl. Acad. Sci. U.S.A.

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Enveloped viruses such as HIV and members of the paramyxovirus family use metastable, proteinaceous fusion machineries to merge the viral envelope with cellular membranes for infection. A hallmark of the fusogenic glycoproteins of these pathogens is refolding into a thermodynamically highly stable fusion core structure composed of six antiparallel α-helices, and this structure is considered instrumental for pore opening and/or enlargement. Using a paramyxovirus fusion (F) protein, we tested this paradigm by engineering covalently restricted F proteins that are predicted to be unable to close the six-helix bundle core structure fully. Several candidate bonds formed efficiently, resulting in F trimers and higher-order complexes containing covalently linked dimers. The engineered F complexes were incorporated into recombinant virions efficiently and were capable of refolding into a postfusion conformation without temporary or permanent disruption of the disulfide bonds. They efficiently formed fusion pores based on virus replication and quantitative cell-to-cell and virus-to-cell fusion assays. Complementation of these F mutants with a monomeric, fusion-inactive F variant enriched the F oligomers for heterotrimers containing a single disulfide bond, without affecting fusion complementation profiles compared with standard F protein. Our demonstration that complete closure of the fusion core does not drive paramyxovirus entry may aid the design of strategies for inhibiting virus entry. membrane fusion | measles virus M embrane fusion is an essential process in eukaryotic cell biology. Examples range from fusion of lipid vesicles to sustain intracellular transport along secretory and endocytotic pathways to cell fusion in fertilization and development and to the fusion of viral with cellular membranes resulting in viral infection. Because there are several high-energy barriers (1), lipid membranes do not merge spontaneously under physiological conditions and therefore require the aid of auxiliary proteins to induce membrane stress and lower the activation energy for lipid merger. For vesicular transport, for instance, soluble N-ethylmaleimide-sensitive factor-activating protein receptor (SNARE) proteins resident in both the target and donor membrane mediate the process (2). Two fundamental differences distinguish cellular fusion machineries from viral fusogenic membrane glycoproteins (vFMGs), which mediate the entry of enveloped viruses by the fusion of the envelope with cellular membranes: (i) vFMGs do not require adapter proteins but insert a fusion peptide domain into the target membrane; and (ii) vFMGs fold into metastable prefusion conformations, obviating the dependence on external energy sources. Three distinct types of viral fusion (F) proteins have been classified: class I vFMGs are found, among others, on influenza virus, retroviruses, and paramyxoviruses; class II proteins are present on alpha-and flaviviruses; and class III proteins mediate herpes-and rhabdovirus entry (reviewed in ref.3).Once the fusion p...

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“…It is known that in eukaryotes, this process is mediated by viral proteins, which help the virus introduce its genetic material into the host cells [14,15]. The first step in a cell infection consists in the binding of certain proteins with specific receptors on the membrane, which can be either proteins, lipids or carbohydrates.…”

Section: Introductionmentioning

confidence: 99%

Behaviour of a peptide sequence from the GB virus C/hepatitis G virus E2 protein in Langmuir monolayers: Its interaction with phospholipid membrane models

Pérez-López¹,

Nieto-Suárez²,

Mestres³

et al. 2009

Biophysical Chemistry

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Virus membrane fusion

Cited by 195 publications

References 50 publications

Molecular Architecture of the Bipartite Fusion Loops of Vesicular Stomatitis Virus Glycoprotein G, a Class III Viral Fusion Protein

Molecular Architecture of the Bipartite Fusion Loops of Vesicular Stomatitis Virus Glycoprotein G, a Class III Viral Fusion Protein

Efficient replication of a paramyxovirus independent of full zippering of the fusion protein six-helix bundle domain

Behaviour of a peptide sequence from the GB virus C/hepatitis G virus E2 protein in Langmuir monolayers: Its interaction with phospholipid membrane models

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