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A proline insertion-deletion in the spike glycoprotein fusion peptide of mouse hepatitis virus strongly alters neuropathology

Singh, Manmeet and Kishore, Abhinoy and Maity, Dibyajyoti and Sunanda, Punnepalli and Krishnarjuna, Bankala and Vappala, Sreeparna and Raghothama, Srinivasarao and Kenyon, Lawrence C. and Pal, Debnath and Das Sarma, Jayasri (2019) A proline insertion-deletion in the spike glycoprotein fusion peptide of mouse hepatitis virus strongly alters neuropathology. In: JOURNAL OF BIOLOGICAL CHEMISTRY, 294 (20). pp. 8064-8087.


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Official URL: http://doi.org/ 10.1074/jbc.RA118.004418


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.

Item Type: Journal Article
Additional Information: copyright for this article belongs to JOURNAL OF BIOLOGICAL CHEMISTRY
Keywords: fusion protein; membrane fusion; plus-stranded RNA virus; neuroinflammation; neurodegeneration; central proline; fusion peptide; mouse hepatitis virus; spike glycoprotein; viral titer; syncytia formation; demyelination; neuropathology
Department/Centre: Division of Chemical Sciences > NMR Research Centre (Formerly Sophisticated Instruments Facility)
Division of Interdisciplinary Sciences > Computational and Data Sciences
Division of Physical & Mathematical Sciences > Mathematics
Date Deposited: 24 Jun 2019 18:23
Last Modified: 24 Jun 2019 18:23
URI: http://eprints.iisc.ac.in/id/eprint/63062

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