Safiriyu, AA and Singh, M and Kishore, A and Mulchandani, V and Maity, D and Behera, A and Sinha, B and Pal, D and Das Sarma, J (2022) Two Consecutive Prolines in the Fusion Peptide of Murine β-Coronavirus Spike Protein Predominantly Determine Fusogenicity and May Be Essential but Not Sufficient to Cause Demyelination. In: Viruses, 14 (4).
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Abstract
Combined in silico, in vitro, and in vivo comparative studies between isogenic-recombinant Mouse-Hepatitis-Virus-RSA59 and its proline deletion mutant, revealed a remarkable contribution of centrally located two consecutive prolines (PP) from Spike protein fusion peptide (FP) in enhancing virus fusogenic and hepato-neuropathogenic potential. To deepen our understanding of the underlying factors, we extend our studies to a non-fusogenic parental virus strain RSMHV2 (P) with a single proline in the FP and its proline inserted mutant, RSMHV2 (PP). Comparative in vitro and in vivo studies between virus strains RSA59(PP), RSMHV2 (P), and RSMHV2 (PP) in the FP demonstrate that the insertion of one proline significantly resulted in enhancing the virus fusogenicity, spread, and consecutive neuropathogenesis. Computational studies suggest that the central PP in Spike FP induces a locally ordered, compact, and rigid structure of the Spike protein in RSMHV2 (PP) compared to RSMHV2 (P), but globally the Spike S2-domain is akin to the parental strain RSA59(PP), the latter being the most flexible showing two potential wells in the energy landscape as observed from the molecular dynamics studies. The critical location of two central prolines of the FP is essential for fusogenicity and pathogenesis making it a potential site for designing antiviral.
| Item Type: | Journal Article |
|---|---|
| Publication: | Viruses |
| Publisher: | NLM (Medline) |
| Additional Information: | The copyright for this article belongs to Authors |
| Keywords: | coronavirus spike glycoprotein; peptide; proline; virus envelope protein, animal; demyelinating disease; genetics; metabolism; mouse, Animals; Demyelinating Diseases; Mice; Peptides; Proline; Spike Glycoprotein, Coronavirus; Viral Envelope Proteins |
| Department/Centre: | Division of Interdisciplinary Sciences > Computational and Data Sciences |
| Date Deposited: | 19 May 2022 09:06 |
| Last Modified: | 19 May 2022 09:06 |
| URI: | https://eprints.iisc.ac.in/id/eprint/72037 |
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