The SARS-CoV-2 spike S375F mutation characterizes the Omicron BA.1 variant

Area of Science:

• Virology
• Molecular Biology
• Evolutionary Biology

Background:

• Omicron variant exhibits distinct virological characteristics, including reduced spike protein cleavage efficacy, ACE2 binding affinity, and fusogenicity.
• The specific mutations responsible for these Omicron spike protein traits remain unidentified.

Purpose of the Study:

• To identify the mutation(s) in the Omicron spike protein responsible for its unique virological characteristics.
• To elucidate the molecular mechanisms underlying Omicron's attenuated properties and rapid human population spread.

Main Methods:

• Molecular phylogenetic analysis to associate mutations with Omicron's spread.
• Analysis of spike protein structure and function, focusing on the receptor-binding domain.
• Investigating interprotomer interactions within the spike trimer.

Main Results:

• The receptor-binding domain of the Omicron spike protein determines its reduced cleavage efficacy, ACE2 binding, and fusogenicity.
• The S375F mutation was identified as a key factor associated with Omicron's widespread transmission.
• The F375 residue engages in an interprotomer pi-pi interaction with H505, reducing spike cleavage efficiency and fusogenicity.

Conclusions:

• The S375F mutation in the Omicron spike protein's receptor-binding domain is critical for its attenuated virological characteristics.
• Molecular interactions within the spike trimer, specifically involving F375, explain Omicron's altered functional properties.
• This study provides molecular insights into the evolutionary emergence of the Omicron variant.