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

Freire, João Miguel; Veiga, Ana Salomé; Torre, Beatriz G. de la; Santos, Nuno C.; Andreu, David; Poian, Andrea T. Da; Castanho, Miguel A. R. B.

doi:10.1002/bip.22266

Cited by 14 publications

(15 citation statements)

References 78 publications

(172 reference statements)

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“…In the case of DENV, it is currently established in the literature that, despite the different entry routes of viral particle internalization, genome release into the cytoplasm occurs through E protein-mediated membrane fusion (Pierson and Kielian 2013). However, recent data from our group support the hypothesis that C protein also participates in the translocation of DENV RNA into the cytoplasm (Freire et al, 2013a,b, Freire et al, 2014.…”

Section: Genome Access To the Cytoplasmmentioning

confidence: 51%

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Receptors and routes of dengue virus entry into the host cells

Cruz-Oliveira

Freire

Conceição

et al. 2015

FEMS Microbiology Reviews

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One-sentence summary: This review addresses the structural rearrangements of dengue virus proteins and their functions during virus entry into the host cells, exploring (a) the cellular elements involved in virus binding to mammalian and mosquito cells, (b) the internalization routes that ultimately lead to virus entry into the cell and (c) the mechanisms by which viral genome gain access to the cytoplasm, including original insights from our recent work that supports the hypothesis that the capsid protein has a role in this process. Editor: Urs Greber ABSTRACTDengue is the most prevalent arthropod-borne viral disease, caused by dengue virus, a member of the Flaviviridae family. Its worldwide incidence is now a major health problem, with 2.5 billion people living in risk areas. In this review, we integrate the structural rearrangements of each viral protein and their functions in all the steps of virus entry into the host cells. We describe in detail the putative receptors and attachment factors in mammalian and mosquito cells, and the recognition of viral immunocomplexes via Fcγ receptor in immune cells. We also discuss that virus internalization might occur through distinct entry pathways, including clathrin-mediated or non-classical clathrin-independent endocytosis, depending on the host cell and virus serotype or strain. The implications of viral maturation in virus entry are also explored. Finally, we discuss the mechanisms of viral genome access to the cytoplasm. This includes the role of low pH-induced conformational changes in the envelope protein that mediate membrane fusion, and original insights raised by our recent work that supports the hypothesis that capsid protein would also be an active player in this process, acting on viral genome translocation into the cytoplasm.

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Section: Genome Access To the Cytoplasmmentioning

confidence: 51%

“…The envelope houses a amorphous ribonucleoprotein complex formed by the capsid (C) protein bound to the positive single-strand RNA (ss-RNA) genome ( Fig. 1) (Kuhn et al, 2002;Zhang et al, 2003a;Freire et al, 2013a). At neutral pH and 28-30…”

Section: Structural Overview Of Denv Particle and Its Componentsmentioning

confidence: 99%

Receptors and routes of dengue virus entry into the host cells

Cruz-Oliveira

Freire

Conceição

et al. 2015

FEMS Microbiology Reviews

Self Cite

248

211

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“…The divergent behavior of pepR and pepM suggests that the cationic domain favors non-covalent nucleic acid binding [26], [27], while the hydrophobic one may favors membrane interaction, perturbation and consequent translocation. It should be noted, however, that these domains cannot be simplistically assigned to the nucleic acid-binding and membrane-binding functionalities of DENV C protein, respectively, since both peptides have the ability to complex ssDNA and to interact with lipids [36], [52].…”

Section: Resultsmentioning

confidence: 99%

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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“…Another example of a multifunctional capsid protein is HIV NC (p7) protein, which, besides forming nucleocapsid shells, has roles in viral uncoating, recognition by restriction factors, and nuclear import and integration [39]. The dengue virus capsid protein, which does not a form shell-like structure [25,28], acts, similar to the histones, to pack RNA in the virion and disrupt nucleosome formation, and its nuclear localization is required to sensitize cells to Fas-induced apoptosis [38]. These proteins are detected [78] and evolve 'through' changes in space when disseminating from one host cell to the other, sometimes even infecting species as different as humans and insects (e.g.…”

Section: Viral Capsid Proteins and Multifunctionality: A Rule Not Anmentioning

confidence: 99%

“…In the present review, we focus on the nucleocapsid proteins of enveloped viruses, of which dengue virus is one example. In dengue virus, the nucleocapsid proteins self-associate in a poorly ordered manner and do not form a shell-like capsid [25][26][27][28]. Instead, they pack the genome in a mixed homogenous amalgamated protein-nucleic acid composite.…”

Section: Introduction: On the Evolution And Diversity Of Viral Capsidmentioning

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

Cited by 14 publications

References 78 publications

Receptors and routes of dengue virus entry into the host cells

Receptors and routes of dengue virus entry into the host cells

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

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