A bundling of viral fusion mechanisms

Kasson, Peter M.; Pande, Vijay S.

doi:10.1073/pnas.1101072108

Cited by 5 publications

(6 citation statements)

References 18 publications

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“…Also, our work suggests the need to revisit the role of the capsid proteins from flaviviruses in the infection cycle. Some concerns about the current view of the viral fusion phenomenon have been already raised [57] , [59] , [60] , and our results support a reappraisal of the possible functionalities of capsid proteins along the viral life cycle. Pierson and Kielian [59] , for instance, stated very recently that, despite the huge and clear advances on the study of DENV organization at a structural and molecular level during the infection cycle steps, the description of this process is still incomplete for stages after hemifusion.…”

Section: Discussionsupporting

confidence: 79%

“…During maturation from early to late endosome, the lipid composition of the endosomal membrane increases in anionic character [54] , an event already proposed as determinant for DENV E protein-mediated endosome-viral envelope fusion [55] . It has been argued, however, that this change in lipid composition may not be sufficient for optimal membrane fusion to occur, as the process is also dependent on the mixture of lipid stalks, hemifusion of lipid bilayers and pore formation [56] , [57] . Based on the experimental evidence gathered in this work, it is reasonable to hypothesize that DENV C protein helps E protein during fusion.…”

Section: Discussionmentioning

confidence: 99%

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Intracellular Nucleic Acid Delivery by the Supercharged Dengue Virus Capsid Protein

et al. 2013

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Supercharged proteins are a recently identified class of proteins that have the ability to efficiently deliver functional macromolecules into mammalian cells. They were first developed as bioengineering products, but were later found in the human proteome. In this work, we show that this class of proteins with unusually high net positive charge is frequently found among viral structural proteins, more specifically among capsid proteins. In particular, the capsid proteins of viruses from the Flaviviridae family have all a very high net charge to molecular weight ratio (> +1.07/kDa), thus qualifying as supercharged proteins. This ubiquity raises the hypothesis that supercharged viral capsid proteins may have biological roles that arise from an intrinsic ability to penetrate cells. Dengue virus capsid protein was selected for a detailed experimental analysis. We showed that this protein is able to deliver functional nucleic acids into mammalian cells. The same result was obtained with two isolated domains of this protein, one of them being able to translocate lipid bilayers independently of endocytic routes. Nucleic acids such as siRNA and plasmids were delivered fully functional into cells. The results raise the possibility that the ability to penetrate cells is part of the native biological functions of some viral capsid proteins.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Intracellular Nucleic Acid Delivery by the Supercharged Dengue Virus Capsid Protein

et al. 2013

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“…The need for a more consistent mechanism of enveloped viral fusion, in particular for dengue virus and other flaviviruses, has been claimed . The recent results described above show that classical models for these fusion mechanisms are over simplistic because only the contribution of envelope proteins is considered, with capsid proteins being overlooked.…”

Section: Proof‐of‐principle Case Study: Dengue Virusmentioning

confidence: 99%

“…The need for a more consistent mechanism of enveloped viral fusion, in particular for dengue virus and other flaviviruses, has been claimed [68][69][70]. The recent results described above show that classical models for these fusion mechanisms are over simplistic [19,20] The 5 0 (capped) and 3 0 UTR are shown with their identified secondary structure [79], as well as the translated region highlighting sequences corresponding to structural and nonstructural proteins.…”

Section: Proof-of-principle Case Study: Dengue Virusmentioning

confidence: 99%

Rethinking the capsid proteins of enveloped viruses: multifunctionality from genome packaging to genome transfection

et al. 2015

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Regardless of the debate on whether there is a place for viruses in the tree of life, it is consensual that they co‐evolve with their hosts under the pressure of genome minimization. The abundance of multifunctional viral structural proteins is a consequence of this pressure. The molecular key to multifunctionality is the existence of intrinsically disordered domains together with ordered domains in the same protein. Capsid proteins, the hallmark of viruses, are not exceptions because they have coexisting ordered and disordered domains that are crucial for multifunctionality. It is also frequent to find supercharged proteins (i.e. proteins for which the net charge per unit molecular mass is > +0.75/kDa) among viral capsid proteins. All flaviviruses having annotated proteins in the ExPASy Viralzone database have supercharged capsid proteins. Moreover, cell‐penetrating sequences/domains are frequent in viral proteins, even when they are not supercharged. Altogether, the findings strongly suggest that the ability to translocate membranes was acquired, conserved and optimized throughout the evolution of some viral proteins as part of their multifunctionality. The fitness of capsid proteins to translocate membranes carrying genomes was experimentally demonstrated with dengue virus capsid protein. This protein is potentially able to help the fusion process and translocate the RNA genome across the hemifused membrane formed by the viral envelope and the endosomal membrane. In addition, one of the cell‐penetrating domains of the capsid protein also has antibacterial activity. This may be reminiscent of parasitic bacteria–bacteria competition for the same host and shed light on the origins of enveloped viruses.

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“…Nevertheless, substantial challenges such as the menace of rising pandemics or the emergence of new strains/serotypes call for a relentless effort in updating our knowledge on virus structure and life cycle as an essential step toward developing novel and more potent therapies (vaccines or antiviral drugs) to fight these threats efficiently …”

mentioning

confidence: 99%

Peptides as models for the structure and function of viral capsid proteins: Insights on dengue virus capsid

et al. 2013

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The structural organization of viral particles is among the most astonishing examples of molecular self-assembly in nature, involving proteins, nucleic acids, and, sometimes, lipids. Proper assembly is essential to produce well structured infectious virions. A great variety of structural arrangements can be found in viral particles. Nucleocapsids, for instance, may display highly ordered geometric shapes or consist in macroscopically amorphous packs of the viral genome. Alphavirus and flavivirus are viral genera that exemplify these extreme cases, the former comprising viral particles structured with a T = 4 icosahedral symmetry, whereas flavivirus capsids have no regular geometry. Dengue virus is a member of flavivirus genus and is used in this article to illustrate how viral protein-derived peptides can be used advantageously over full-length proteins to unravel the foundations of viral supramolecular assemblies. Membrane- and viral RNA-binding data of capsid protein-derived dengue virus peptides are used to explain the amorphous organization of the viral capsid. Our results combine bioinformatic and spectroscopic approaches using two- or three-component peptide and/or nucleic acid and/or lipid systems.

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A bundling of viral fusion mechanisms

Cited by 5 publications

References 18 publications

Intracellular Nucleic Acid Delivery by the Supercharged Dengue Virus Capsid Protein

Intracellular Nucleic Acid Delivery by the Supercharged Dengue Virus Capsid Protein

Rethinking the capsid proteins of enveloped viruses: multifunctionality from genome packaging to genome transfection

Peptides as models for the structure and function of viral capsid proteins: Insights on dengue virus capsid

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