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Structure of the dimerization domain of the rabies virus phosphoprotein.

ABSTRACT: The crystal structure of the dimerization domain of rabies virus phosphoprotein was determined. The monomer consists of two alpha-helices that make a helical hairpin held together mainly by hydrophobic interactions. The monomer has a hydrophilic and a hydrophobic face, and in the dimer two monomers pack together through their hydrophobic surfaces. This structure is very different from the dimerization domain of the vesicular stomatitis virus phosphoprotein and also from the tetramerization domain of the Sendai virus phosphoprotein, suggesting that oligomerization is conserved but not structure.

SUBMITTER: Ivanov I

PROVIDER: S-EPMC2838143 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Structure of the dimerization domain of the rabies virus phosphoprotein.

Ivanov Ivan I Crépin Thibaut T Jamin Marc M Ruigrok Rob W H RW

Journal of virology 20100120 7

The crystal structure of the dimerization domain of rabies virus phosphoprotein was determined. The monomer consists of two alpha-helices that make a helical hairpin held together mainly by hydrophobic interactions. The monomer has a hydrophilic and a hydrophobic face, and in the dimer two monomers pack together through their hydrophobic surfaces. This structure is very different from the dimerization domain of the vesicular stomatitis virus phosphoprotein and also from the tetramerization domai ...[more]

PMID: 20089657

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Project description:Rabies virus (RABV) P gene mRNA encodes five in-frame start codons, resulting in expression of full-length P protein (P1) and N-terminally truncated P proteins (tPs), designated P2, P3, P4, and P5. Despite the fact that some tPs are known as interferon (IFN) antagonists, the importance of tPs in the pathogenesis of RABV is still unclear. In this study, to examine whether tPs contribute to pathogenesis, we exploited a reverse genetics approach to generate CE(NiP)?P2-5, a mutant of pathogenic CE(NiP) in which the P gene was mutated by replacing all of the start codons (AUG) for tPs with AUA. We confirmed that while CE(NiP) expresses detectable levels of P2 and P3, CE(NiP)?P2-5 has an impaired ability to express these tPs. After intramuscular inoculation, CE(NiP)?P2-5 caused significantly lower morbidity and mortality rates in mice than did CE(NiP), indicating that tPs play a critical role in RABV neuroinvasiveness. Further examinations revealed that this less neuroinvasive phenotype of CE(NiP)?P2-5 correlates with its impaired ability to replicate in muscle cells, indicative of the importance of tPs in viral replication in muscle cells. We also demonstrated that CE(NiP)?P2-5 infection induced a higher level of Ifn-? gene expression in muscle cells than did CE(NiP) infection, consistent with the results of an IFN-? promoter reporter assay suggesting that all tPs function to antagonize IFN induction in muscle cells. Taken together, our findings strongly suggest that tPs promote viral replication in muscle cells through their IFN antagonist activities and thereby support infection of peripheral nerves.Despite the fact that previous studies have demonstrated that P2 and P3 of RABV have IFN antagonist activities, the actual importance of tPs in pathogenesis has remained unclear. Here, we provide the first evidence that tPs contribute to the pathogenesis of RABV, especially its neuroinvasiveness. Our results also show the mechanism underlying the neuroinvasiveness driven by tPs, highlighting the importance of their IFN antagonist activities, which support viral replication in muscle cells.

Dataset Information

Structure of the dimerization domain of the rabies virus phosphoprotein.

Publications

Structure of the dimerization domain of the rabies virus phosphoprotein.

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