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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

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 fuso...

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Autores principales: Safiriyu, Abass Alao, Singh, Manmeet, Kishore, Abhinoy, Mulchandani, Vaishali, Maity, Dibyajyoti, Behera, Amrutamaya, Sinha, Bidisha, Pal, Debnath, Das Sarma, Jayasri
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9031231/
https://www.ncbi.nlm.nih.gov/pubmed/35458565
http://dx.doi.org/10.3390/v14040834
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author Safiriyu, Abass Alao
Singh, Manmeet
Kishore, Abhinoy
Mulchandani, Vaishali
Maity, Dibyajyoti
Behera, Amrutamaya
Sinha, Bidisha
Pal, Debnath
Das Sarma, Jayasri
author_facet Safiriyu, Abass Alao
Singh, Manmeet
Kishore, Abhinoy
Mulchandani, Vaishali
Maity, Dibyajyoti
Behera, Amrutamaya
Sinha, Bidisha
Pal, Debnath
Das Sarma, Jayasri
author_sort Safiriyu, Abass Alao
collection PubMed
description 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.
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spelling pubmed-90312312022-04-23 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 Safiriyu, Abass Alao Singh, Manmeet Kishore, Abhinoy Mulchandani, Vaishali Maity, Dibyajyoti Behera, Amrutamaya Sinha, Bidisha Pal, Debnath Das Sarma, Jayasri Viruses Article 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. MDPI 2022-04-17 /pmc/articles/PMC9031231/ /pubmed/35458565 http://dx.doi.org/10.3390/v14040834 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Safiriyu, Abass Alao
Singh, Manmeet
Kishore, Abhinoy
Mulchandani, Vaishali
Maity, Dibyajyoti
Behera, Amrutamaya
Sinha, Bidisha
Pal, Debnath
Das Sarma, Jayasri
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9031231/
https://www.ncbi.nlm.nih.gov/pubmed/35458565
http://dx.doi.org/10.3390/v14040834
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