Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 297, Issue 4, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.jbc.2021.101127
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Funding
- Frederick National Laboratory for Cancer Research
- NIH [HHSN261200800001]
- NCI's National CryoEM Facility at the Frederick National Laboratory for Cancer Research [HSSN261200800001E]
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The spike protein of SARS-CoV-2 is susceptible to unfolding under certain conditions, which affects its immunogenicity. Although the native-like conformation can be reacquired, longer storage leads to decreased antibody binding. Monitoring the integrity of the spike protein is crucial for the development of effective COVID-19 vaccines.
The SARS-CoV-2 spike is the primary target of virusneutralizing antibodies and critical to the development of effective vaccines against COVID-19. Here, we demonstrate that the prefusion-stabilized two-proline S2P spike-widely employed for laboratory work and clinical studies-unfolds when stored at 4 degrees C, physiological pH, as observed by electron microscopy (EM) and differential scanning calorimetry, but that its trimeric, native-like conformation can be reacquired by low pH treatment. When stored for approximately 1 week, this unfolding does not significantly alter antigenic characteristics; however, longer storage diminishes antibody binding, and month-old spike elicits virtually no neutralization in mice despite inducing high ELISA-binding titers. Cryo-EM structures reveal the folded fraction of spike to decrease with aging; however, its structure remains largely similar, although with varying mobility of the receptor-binding domain. Thus, the SARS-CoV-2 spike is susceptible to unfolding, which affects immunogenicity, highlighting the need to monitor its integrity.
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