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Stabilizing the closed SARS-CoV-2 spike trimer.
Jarek Juraszek1, Lucy Rutten1, Sven Blokland1
1Janssen Vaccines & Prevention B.V., Archimedesweg 4-6, Leiden, The Netherlands.
Nature Communications
|January 12, 2021
Summary
Researchers engineered a more stable SARS-CoV-2 spike (S) protein trimer for vaccine development. This improved S protein design enhances yield and stability, crucial for effective immunogens and diagnostics.
Area of Science:
- Virology
- Structural Biology
- Immunology
Background:
- The SARS-CoV-2 spike (S) protein is a key target for vaccines.
- Class I fusion proteins like S are inherently unstable, often refolding prematurely.
- This instability reduces immunogenicity and complicates production of prefusion trimers.
Purpose of the Study:
- To design stabilized, soluble SARS-CoV-2 S protein trimers.
- To enhance S protein yields and immunogenic properties for vaccine development.
- To elucidate the structural basis of S protein stability.
Main Methods:
- Structure-based design incorporating single point mutations and disulfide bridges.
- Identification of critical regions for S protein stability (HR1, SD1, position 614).
- Cryo-electron microscopy (cryo-EM) to determine the structure of the designed S variant.
Main Results:
- Developed a stable, closed S-closed variant with 6.4-fold higher expression than the parent construct.
- Introduced interprotomeric mutations and disulfide bridges for enhanced stability.
- Cryo-EM confirmed a correctly folded, predominantly closed prefusion conformation.
Conclusions:
- Engineered soluble S protein trimers exhibit significantly improved stability and expression.
- Understanding S protein structure-stability relationships aids vaccine design.
- The stable S protein variant supports vaccine development and serological diagnostics.
