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Proline–Proline Dyad in the Fusion Peptide of the Murine β–Coronavirus Spike Protein’s S2 Domain Modulates Its Neuroglial Tropism

The β-Coronavirus mouse hepatitis virus (MHV-A59)-RSA59 has a patent stretch of fusion peptide (FP) containing two consecutive central prolines (PP) in the S2 domain of the Spike protein. Our previous studies compared the PP-containing fusogenic-demyelinating strain RSA59(PP) to its one proline-dele...

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Autores principales: Safiriyu, Abass Alao, Mulchandani, Vaishali, Anakkacheri, Mohammed Nahaf, Pal, Debnath, Das Sarma, Jayasri
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865228/
https://www.ncbi.nlm.nih.gov/pubmed/36680255
http://dx.doi.org/10.3390/v15010215
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author Safiriyu, Abass Alao
Mulchandani, Vaishali
Anakkacheri, Mohammed Nahaf
Pal, Debnath
Das Sarma, Jayasri
author_facet Safiriyu, Abass Alao
Mulchandani, Vaishali
Anakkacheri, Mohammed Nahaf
Pal, Debnath
Das Sarma, Jayasri
author_sort Safiriyu, Abass Alao
collection PubMed
description The β-Coronavirus mouse hepatitis virus (MHV-A59)-RSA59 has a patent stretch of fusion peptide (FP) containing two consecutive central prolines (PP) in the S2 domain of the Spike protein. Our previous studies compared the PP-containing fusogenic-demyelinating strain RSA59(PP) to its one proline-deleted mutant strain RSA59(P) and one proline-containing non-fusogenic non-demyelinating parental strain RSMHV2(P) to its one proline inserted mutant strain RSMHV2(PP). These studies highlighted the crucial role of PP in fusogenicity, hepato-neuropathogenesis, and demyelination. Computational studies combined with biophysical data indicate that PP at the center of the FP provides local rigidity while imparting global fluctuation to the Spike protein that enhances the fusogenic properties of RSA59(PP) and RSMHV2(PP). To elaborate on the understanding of the role of PP in the FP of MHV, the differential neuroglial tropism of the PP and P mutant strains was investigated. Comparative studies demonstrated that PP significantly enhances the viral tropism for neurons, microglia, and oligodendrocytes. PP, however, is not essential for viral tropism for either astroglial or oligodendroglial precursors or the infection of meningeal fibroblasts in the blood–brain and blood–CSF barriers. PP in the fusion domain is critical for promoting gliopathy, making it a potential region for designing antivirals for neuro-COVID therapy.
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spelling pubmed-98652282023-01-22 Proline–Proline Dyad in the Fusion Peptide of the Murine β–Coronavirus Spike Protein’s S2 Domain Modulates Its Neuroglial Tropism Safiriyu, Abass Alao Mulchandani, Vaishali Anakkacheri, Mohammed Nahaf Pal, Debnath Das Sarma, Jayasri Viruses Article The β-Coronavirus mouse hepatitis virus (MHV-A59)-RSA59 has a patent stretch of fusion peptide (FP) containing two consecutive central prolines (PP) in the S2 domain of the Spike protein. Our previous studies compared the PP-containing fusogenic-demyelinating strain RSA59(PP) to its one proline-deleted mutant strain RSA59(P) and one proline-containing non-fusogenic non-demyelinating parental strain RSMHV2(P) to its one proline inserted mutant strain RSMHV2(PP). These studies highlighted the crucial role of PP in fusogenicity, hepato-neuropathogenesis, and demyelination. Computational studies combined with biophysical data indicate that PP at the center of the FP provides local rigidity while imparting global fluctuation to the Spike protein that enhances the fusogenic properties of RSA59(PP) and RSMHV2(PP). To elaborate on the understanding of the role of PP in the FP of MHV, the differential neuroglial tropism of the PP and P mutant strains was investigated. Comparative studies demonstrated that PP significantly enhances the viral tropism for neurons, microglia, and oligodendrocytes. PP, however, is not essential for viral tropism for either astroglial or oligodendroglial precursors or the infection of meningeal fibroblasts in the blood–brain and blood–CSF barriers. PP in the fusion domain is critical for promoting gliopathy, making it a potential region for designing antivirals for neuro-COVID therapy. MDPI 2023-01-12 /pmc/articles/PMC9865228/ /pubmed/36680255 http://dx.doi.org/10.3390/v15010215 Text en © 2023 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
Mulchandani, Vaishali
Anakkacheri, Mohammed Nahaf
Pal, Debnath
Das Sarma, Jayasri
Proline–Proline Dyad in the Fusion Peptide of the Murine β–Coronavirus Spike Protein’s S2 Domain Modulates Its Neuroglial Tropism
title Proline–Proline Dyad in the Fusion Peptide of the Murine β–Coronavirus Spike Protein’s S2 Domain Modulates Its Neuroglial Tropism
title_full Proline–Proline Dyad in the Fusion Peptide of the Murine β–Coronavirus Spike Protein’s S2 Domain Modulates Its Neuroglial Tropism
title_fullStr Proline–Proline Dyad in the Fusion Peptide of the Murine β–Coronavirus Spike Protein’s S2 Domain Modulates Its Neuroglial Tropism
title_full_unstemmed Proline–Proline Dyad in the Fusion Peptide of the Murine β–Coronavirus Spike Protein’s S2 Domain Modulates Its Neuroglial Tropism
title_short Proline–Proline Dyad in the Fusion Peptide of the Murine β–Coronavirus Spike Protein’s S2 Domain Modulates Its Neuroglial Tropism
title_sort proline–proline dyad in the fusion peptide of the murine β–coronavirus spike protein’s s2 domain modulates its neuroglial tropism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9865228/
https://www.ncbi.nlm.nih.gov/pubmed/36680255
http://dx.doi.org/10.3390/v15010215
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