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Enhanced local symmetry interactions globally stabilize a mutant virus capsid that maintains infectivity and capsid dynamics.

ABSTRACT: Structural transitions in viral capsids play a critical role in the virus life cycle, including assembly, disassembly, and release of the packaged nucleic acid. Cowpea chlorotic mottle virus (CCMV) undergoes a well-studied reversible structural expansion in vitro in which the capsid expands by 10%. The swollen form of the particle can be completely disassembled by increasing the salt concentration to 1 M. Remarkably, a single-residue mutant of the CCMV N-terminal arm, K42R, is not susceptible to dissociation in high salt (salt-stable CCMV [SS-CCMV]) and retains 70% of wild-type infectivity. We present the combined structural and biophysical basis for the chemical stability and viability of the SS-CCMV particles. A 2.7-A resolution crystal structure of the SS-CCMV capsid shows an addition of 660 new intersubunit interactions per particle at the center of the 20 hexameric capsomeres, which are a direct result of the K42R mutation. Protease-based mapping experiments of intact particles demonstrate that both the swollen and closed forms of the wild-type and SS-CCMV particles have highly dynamic N-terminal regions, yet the SS-CCMV particles are more resistant to degradation. Thus, the increase in SS-CCMV particle stability is a result of concentrated tethering of subunits at a local symmetry interface (i.e., quasi-sixfold axes) that does not interfere with the function of other key symmetry interfaces (i.e., fivefold, twofold, quasi-threefold axes). The result is a particle that is still dynamic but insensitive to high salt due to a new series of bonds that are resistant to high ionic strength and preserve the overall particle structure.

SUBMITTER: Speir JA

PROVIDER: S-EPMC1440388 | biostudies-literature | 2006 Apr

REPOSITORIES: biostudies-literature

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Enhanced local symmetry interactions globally stabilize a mutant virus capsid that maintains infectivity and capsid dynamics.

Speir Jeffrey A JA Bothner Brian B Qu Chunxu C Willits Deborah A DA Young Mark J MJ Johnson John E JE

Journal of virology 20060401 7

Structural transitions in viral capsids play a critical role in the virus life cycle, including assembly, disassembly, and release of the packaged nucleic acid. Cowpea chlorotic mottle virus (CCMV) undergoes a well-studied reversible structural expansion in vitro in which the capsid expands by 10%. The swollen form of the particle can be completely disassembled by increasing the salt concentration to 1 M. Remarkably, a single-residue mutant of the CCMV N-terminal arm, K42R, is not susceptible to ...[more]

PMID: 16537626

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Project description:ImportanceAssumption of a well-mixed population during modeling is often erroneously made without due analysis of its validity. Ignoring the importance of the geo-spatial granularity at which the data is collected could have significant implications on the quality of forecasts and the actionable clinical recommendations that are based on it.ObjectiveThis paper's primary objective is to test the hypothesis that the characteristic dynamics defining the trajectory of the pandemic in a region is lost when the data is aggregated and modeled at higher geo-spatial levels.DesignWe use publicly available confirmed SARS-CoV-2 cases and deaths from January 1st, 2020 to August 3rd, 2020 in the United States at different geo-spatial granularities to conduct our experiments. To understand the impact of this hypothesis, the output of this study was implemented in Tampa General Hospital (TGH) to provide resource demand forecast.ResultsThe Mean Absolute Percentage Error (MAPE) in the forecast confirmed cases can be 30% higher for modeling at the state-level than aggregating model results at the scale of counties or clusters of counties. Similarly, modeling at a state-level and crafting policy decisions based on them may not be effective - county-level forecasts made by partitioning state-level forecasts are 3x worse for confirmed cases and 20x worse for deaths relative to the same model at the county level. By leveraging these results, TGH was able to accurately allocate clinical resources to tackle COVID-19 cases, continue elective surgical procedures largely uninterrupted and avoid costly construction of overflow capacity in the first two epidemic waves.Conclusions and relevanceAccurate forecasting at the county level requires hyper-local modeling with county resolution. State-level modeling does not accurately predict community spread in smaller sub-regions because state populations are not well mixed, resulting in large prediction errors. Actionable decisions such as deciding whether to cancel planned surgeries or construct overflow capacity require models with local specificity.

Dataset Information

Enhanced local symmetry interactions globally stabilize a mutant virus capsid that maintains infectivity and capsid dynamics.

Publications

Enhanced local symmetry interactions globally stabilize a mutant virus capsid that maintains infectivity and capsid dynamics.

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