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Flexible Connectors between Capsomer Subunits that Regulate Capsid Assembly.

ABSTRACT: Viruses build icosahedral capsids of specific size and shape by regulating the spatial arrangement of the hexameric and pentameric protein capsomers in the growing shell during assembly. In the T=7 capsids of Escherichia coli bacteriophage HK97 and other phages, 60 capsomers are hexons, while the rest are pentons that are correctly positioned during assembly. Assembly of the HK97 capsid to the correct size and shape has been shown to depend on specific ionic contacts between capsomers. We now describe additional ionic interactions within capsomers that also regulate assembly. Each is between the long hairpin, the "E-loop," that extends from one subunit to the adjacent subunit within the same capsomer. Glutamate E153 on the E-loop and arginine R210 on the adjacent subunit's backbone alpha-helix form salt bridges in hexamers and pentamers. Mutations that disrupt these salt bridges were lethal for virus production, because the mutant proteins assembled into tubes or sheets instead of capsids. X-ray structures show that the E153-R210 links are flexible and maintained during maturation despite radical changes in capsomer shape. The E153-R210 links appear to form early in assembly to enable capsomers to make programmed changes in their shape during assembly. The links also prevent flattening of capsomers and premature maturation. Mutant phenotypes and modeling support an assembly model in which flexible E153-R210 links mediate capsomer shape changes that control where pentons are placed to create normal-sized capsids. The E-loop may be conserved in other systems in order to play similar roles in regulating assembly.

SUBMITTER: Hasek ML

PROVIDER: S-EPMC5555079 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Flexible Connectors between Capsomer Subunits that Regulate Capsid Assembly.

Hasek Mary L ML Maurer Joshua B JB Hendrix Roger W RW Duda Robert L RL

Journal of molecular biology 20170710 16

Viruses build icosahedral capsids of specific size and shape by regulating the spatial arrangement of the hexameric and pentameric protein capsomers in the growing shell during assembly. In the T=7 capsids of Escherichia coli bacteriophage HK97 and other phages, 60 capsomers are hexons, while the rest are pentons that are correctly positioned during assembly. Assembly of the HK97 capsid to the correct size and shape has been shown to depend on specific ionic contacts between capsomers. We now de ...[more]

PMID: 28705762

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Project description:Directed self-assembly of designed viral capsids holds significant potential for applications in materials science and medicine. However, the complexity of preparing these systems for assembly and the difficulty of quantitative experimental measurements on the assembly process have limited access to critical mechanistic questions that dictate the final product yields and isomorphic forms. Molecular simulations provide a means of elucidating self-assembly of viral proteins into icosahedral capsids and are the focus of the present study. Using geometrically realistic coarse-grained models with specialized molecular dynamics methods, we delineate conditions of temperature and coat protein concentration that lead to the spontaneous self-assembly of T = 1 and T = 3 icosahedral capsids. In addition to the primary product of icosahedral capsids, we observe a ubiquitous presence of nonicosahedral yet highly symmetric and enclosed aberrant capsules in both T = 1 and T = 3 systems. This polymorphism in assembly products recapitulates the scope and morphology of particle types that have been observed in mis-assembly experiments of virus capsids. Moreover, we find that this structural polymorphism in the end point structures is an inherent property of the coat proteins and arises from condition-dependent kinetic mechanisms that are independent of the elemental mechanisms of capsid growth (as long as the building blocks of the coat proteins are all monomeric, dimeric, or trimeric) and the capsid T number. The kinetic mechanisms responsible for self-assembly of icosahedral capsids and aberrant capsules are deciphered; the self-assembly of icosahedral capsids requires a high level of assembly fidelity, whereas self-assembly of nonicosahedral capsules is a consequence of an off-pathway mechanism that is prevalent under nonoptimal conditions of temperature or protein concentration during assembly. The latter case involves kinetically trapped dislocations of pentamer-templated proteins with hexameric organization. These findings provide insights into the complex processes that govern viral capsid assembly and suggest some features of the assembly process that can be exploited to control the assembly of icosahedral capsids and nonicosahedral capsules.

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Flexible Connectors between Capsomer Subunits that Regulate Capsid Assembly.

Publications

Flexible Connectors between Capsomer Subunits that Regulate Capsid Assembly.

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