Structural Dynamics and Molecular Evolution of the SARS-CoV-2 Spike Protein

The ongoing coronavirus disease 2019 (COVID-19) pandemic demonstrates the threat posed by novel coronaviruses to human health. Coronaviruses share a highly conserved cell entry mechanism mediated by the spike protein, the sole product of the S gene. The ongoing coronavirus disease 2019 (COVID-19) pandemic demonstrates the threat posed by novel coronaviruses to human health. Coronaviruses share a highly conserved cell entry mechanism mediated by the spike protein, the sole product of the S gene. The structural dynamics by which the spike protein orchestrates infection illuminate how antibodies neutralize virions and how S mutations contribute to viral fitness. Here, we review the process by which spike engages its proteinaceous receptor, angiotensin converting enzyme 2 (ACE2), and how host proteases prime and subsequently enable efficient membrane fusion between virions and target cells. We highlight mutations common among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern and discuss implications for cell entry. Ultimately, we provide a model by which sarbecoviruses are activated for fusion competency and offer a framework for understanding the interplay between humoral immunity and the molecular evolution of the SARS-CoV-2 Spike. In particular, we emphasize the relevance of the Canyon Hypothesis (M. G. Rossmann, J Biol Chem 264:14587-14590, 1989) for understanding evolutionary trajectories of viral entry proteins during sustained intraspecies transmission of a novel viral pathogen.

Automated summary

This article reviews the process of binding between the spike protein of coronaviruses and their receptor, as well as the role of host proteases in promoting viral-cell membrane fusion. The implications of SARS-CoV-2 mutations on cell entry are discussed, along with a model for activating fusion competency in sarbecoviruses and a framework for understanding the interplay between humoral immunity and the molecular evolution of the SARS-CoV-2 Spike. The relevance of the Canyon Hypothesis in understanding the evolutionary trajectories of viral entry proteins during sustained intraspecies transmission of a novel viral pathogen is emphasized.