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D614G mutation in the SARS-CoV-2 spike protein enhances viral fitness by desensitizing it to temperature-dependent denaturation

The D614G mutation in the spike protein of SARS-CoV-2 alters the fitness of the virus, leading to the dominant form observed in the COVID-19 pandemic. However, the molecular basis of the mechanism by which this mutation enhances fitness is not clear. Here we demonstrated by cryo-electron microscopy...

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Autores principales: Yang, Tzu-Jing, Yu, Pei-Yu, Chang, Yuan-Chih, Hsu, Shang-Te Danny
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460419/
https://www.ncbi.nlm.nih.gov/pubmed/34563540
http://dx.doi.org/10.1016/j.jbc.2021.101238
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author Yang, Tzu-Jing
Yu, Pei-Yu
Chang, Yuan-Chih
Hsu, Shang-Te Danny
author_facet Yang, Tzu-Jing
Yu, Pei-Yu
Chang, Yuan-Chih
Hsu, Shang-Te Danny
author_sort Yang, Tzu-Jing
collection PubMed
description The D614G mutation in the spike protein of SARS-CoV-2 alters the fitness of the virus, leading to the dominant form observed in the COVID-19 pandemic. However, the molecular basis of the mechanism by which this mutation enhances fitness is not clear. Here we demonstrated by cryo-electron microscopy that the D614G mutation resulted in increased propensity of multiple receptor-binding domains (RBDs) in an upward conformation poised for host receptor binding. Multiple substates within the one RBD-up or two RBD-up conformational space were determined. According to negative staining electron microscopy, differential scanning calorimetry, and differential scanning fluorimetry, the most significant impact of the mutation lies in its ability to eliminate the unusual cold-induced unfolding characteristics and to significantly increase the thermal stability under physiological pH. The D614G spike variant also exhibited exceptional long-term stability when stored at 37 °C for up to 2 months. Our findings shed light on how the D614G mutation enhances the infectivity of SARS-CoV-2 through a stabilizing mutation and suggest an approach for better design of spike protein-based conjugates for vaccine development.
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spelling pubmed-84604192021-09-24 D614G mutation in the SARS-CoV-2 spike protein enhances viral fitness by desensitizing it to temperature-dependent denaturation Yang, Tzu-Jing Yu, Pei-Yu Chang, Yuan-Chih Hsu, Shang-Te Danny J Biol Chem Accelerated Communication The D614G mutation in the spike protein of SARS-CoV-2 alters the fitness of the virus, leading to the dominant form observed in the COVID-19 pandemic. However, the molecular basis of the mechanism by which this mutation enhances fitness is not clear. Here we demonstrated by cryo-electron microscopy that the D614G mutation resulted in increased propensity of multiple receptor-binding domains (RBDs) in an upward conformation poised for host receptor binding. Multiple substates within the one RBD-up or two RBD-up conformational space were determined. According to negative staining electron microscopy, differential scanning calorimetry, and differential scanning fluorimetry, the most significant impact of the mutation lies in its ability to eliminate the unusual cold-induced unfolding characteristics and to significantly increase the thermal stability under physiological pH. The D614G spike variant also exhibited exceptional long-term stability when stored at 37 °C for up to 2 months. Our findings shed light on how the D614G mutation enhances the infectivity of SARS-CoV-2 through a stabilizing mutation and suggest an approach for better design of spike protein-based conjugates for vaccine development. American Society for Biochemistry and Molecular Biology 2021-09-24 /pmc/articles/PMC8460419/ /pubmed/34563540 http://dx.doi.org/10.1016/j.jbc.2021.101238 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Accelerated Communication
Yang, Tzu-Jing
Yu, Pei-Yu
Chang, Yuan-Chih
Hsu, Shang-Te Danny
D614G mutation in the SARS-CoV-2 spike protein enhances viral fitness by desensitizing it to temperature-dependent denaturation
title D614G mutation in the SARS-CoV-2 spike protein enhances viral fitness by desensitizing it to temperature-dependent denaturation
title_full D614G mutation in the SARS-CoV-2 spike protein enhances viral fitness by desensitizing it to temperature-dependent denaturation
title_fullStr D614G mutation in the SARS-CoV-2 spike protein enhances viral fitness by desensitizing it to temperature-dependent denaturation
title_full_unstemmed D614G mutation in the SARS-CoV-2 spike protein enhances viral fitness by desensitizing it to temperature-dependent denaturation
title_short D614G mutation in the SARS-CoV-2 spike protein enhances viral fitness by desensitizing it to temperature-dependent denaturation
title_sort d614g mutation in the sars-cov-2 spike protein enhances viral fitness by desensitizing it to temperature-dependent denaturation
topic Accelerated Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460419/
https://www.ncbi.nlm.nih.gov/pubmed/34563540
http://dx.doi.org/10.1016/j.jbc.2021.101238
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