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A modelling paradigm for RNA virus assembly.

ABSTRACT: Virus assembly, a key stage in any viral life cycle, had long been considered to be primarily driven by protein-protein interactions and nonspecific interactions between genomic RNA and capsid protein. We review here a modelling paradigm for RNA virus assembly that illustrates the crucial roles of multiple dispersed, specific interactions between viral genomes and coat proteins in capsid assembly. The model reveals how multiple sequence-structure motifs in the genomic RNA, termed packaging signals, with a shared coat protein recognition motif enable viruses to overcome a viral assembly-equivalent of Levinthal's Paradox in protein folding. The fitness advantages conferred by this mechanism suggest that it should be widespread in viruses, opening up new perspectives on viral evolution and anti-viral therapy.

SUBMITTER: Twarock R

PROVIDER: S-EPMC6281560 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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A modelling paradigm for RNA virus assembly.

Twarock Reidun R Bingham Richard J RJ Dykeman Eric C EC Stockley Peter G PG

Current opinion in virology 20180802

Virus assembly, a key stage in any viral life cycle, had long been considered to be primarily driven by protein-protein interactions and nonspecific interactions between genomic RNA and capsid protein. We review here a modelling paradigm for RNA virus assembly that illustrates the crucial roles of multiple dispersed, specific interactions between viral genomes and coat proteins in capsid assembly. The model reveals how multiple sequence-structure motifs in the genomic RNA, termed packaging signa ...[more]

PMID: 30078702

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Project description:BACKGROUND: When purified phagosomes are incubated in the presence of actin under appropriate conditions, microfilaments start growing from the membrane in a process that is affected by ATP and the lipid composition of the membrane. Isolated phagosomes are metabolically active organelles that contain enzymes and metabolites necessary for lipid interconversion. Hence, addition of ATP, lipids, and actin to the system alter the steady-state composition of the phagosomal membrane at the same time that the actin nucleation is initiated. Our aim was to model all these processes in parallel. RESULTS: We compiled detailed experimental data on the effects of different lipids and ATP on actin nucleation and we investigated experimentally lipid interconversion and ATP metabolism in phagosomes by using suitable radioactive compounds.In a first step, a complex lipid network interconnected by chemical reactions catalyzed by known enzymes was modelled in COPASI (Complex Pathway Simulator). However, several lines of experimental evidence indicated that only the phosphatidylinositol branch of the network was active, an observation that dramatically reduced the number of parameters in the model. The results also indicated that a lipid network-independent ATP-consuming activity should be included in the model. When this activity was introduced, the set of differential equations satisfactorily reproduced the experimental data. On the other hand, a molecular mechanism connecting membrane lipids, ATP, and the actin nucleation process is still missing. We therefore adopted a phenomenological (black-box) approach to represent the empirical observations. We proposed that lipids and ATP influence the dynamic interconversion between active and inactive actin nucleation sites. With this simple model, all the experimental data were satisfactorily fitted with a single positive parameter per lipid and ATP. CONCLUSION: By establishing an active 'dialogue' between an initial complex model and experimental observations, we could narrow the set of differential equations and parameters required to characterize the time-dependent changes of metabolites influencing actin nucleation on phagosomes. For this, the global model was dissected into three sub-models: ATP consumption, lipid interconversion, and nucleation of actin on phagosomal membranes. This scheme allowed us to describe this complex system with a relatively small set of differential equations and kinetic parameters that satisfactorily reproduced the experimental data.

Dataset Information

A modelling paradigm for RNA virus assembly.

Publications

A modelling paradigm for RNA virus assembly.

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