A proline insertion-deletion in the spike glycoprotein fusion peptide of mouse hepatitis virus strongly alters neuropathology
| Autor: | Dibyajyoti Maity, Punnepalli Sunanda, Debnath Pal, Bankala Krishnarjuna, Jayasri Das Sarma, Lawrence C. Kenyon, Srinivasarao Raghothama, Abhinoy Kishore, Sreeparna Vappala, Manmeet Singh |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Proline Computational and Data Sciences Biochemistry Microbiology Virus Cell Line 03 medical and health sciences Mice Structure-Activity Relationship Mouse hepatitis virus INDEL Mutation Protein Domains Viral Envelope Proteins Parenchyma Animals Molecular Biology Nuclear Magnetic Resonance Biomolecular chemistry.chemical_classification Syncytium Murine hepatitis virus 030102 biochemistry & molecular biology biology NMR Research Centre (Formerly Sophisticated Instruments Facility) Lipid bilayer fusion Brain Cell Biology biology.organism_classification Fusion protein Molecular biology Meningitis Viral Amino acid 030104 developmental biology chemistry Glycoprotein Mathematics Demyelinating Diseases |
| Zdroj: | J Biol Chem |
| ISSN: | 1083-351X |
| Popis: | Fusion peptides (FPs) in spike proteins are key players mediating early events in cell-to-cell fusion, vital for intercellular viral spread. A proline residue located at the central FP region has often been suggested to have a distinctive role in this fusion event. The spike glycoprotein from strain RSA59 (PP) of mouse hepatitis virus (MHV) contains two central, consecutive prolines in the FP. Here, we report that deletion of one of these proline residues, resulting in RSA59 (P), significantly affected neural cell syncytia formation and viral titers postinfection in vitro. Transcranial inoculation of C57Bl/6 mice with RSA59 (PP) or RSA59 (P) yielded similar degrees of necrotizing hepatitis and meningitis, but only RSA59 (PP) produced widespread encephalitis that extended deeply into the brain parenchyma. By day 6 postinfection, both virus variants were mostly cleared from the brain. Interestingly, inoculation with the RSA59 (P)-carrying MHV significantly reduced demyelination at the chronic stage. We also found that the presence of two consecutive prolines in FP promotes a more ordered, compact, and rigid structure in the spike protein. These effects on FP structure were due to proline's unique stereochemical properties intrinsic to its secondary amino acid structure, revealed by molecular dynamics and NMR experiments. We therefore propose that the differences in the severity of encephalitis and demyelination between RSA59 (PP) and RSA59 (P) arise from the presence or absence, respectively, of the two consecutive prolines in FP. Our studies define a structural determinant of MHV entry in the brain parenchyma important for altered neuropathogenesis. |
| Databáze: | OpenAIRE |
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