Journal Article

SARS-CoV-2 Variants Increase Kinetic Stability of Open Spike Conformations as an Evolutionary Strategy

Shi, Wei, Ding, Shilei, Zhou, Tongqing, Finzi, Andrés, Han, Yang, Mothes, Walther, Lu, Maolin, Yang, Ziwei, Kwong, Peter D.

2022

Overview

SARS-CoV-2 surface S glycoprotein—the target of antibodies and vaccines—is responsible for binding to the cellular receptor hACE2. The interactions between S and hACE2 trigger structural rearrangements of S from closed to open conformations prerequisite for virus entry. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) harbor mutations in the spike (S) glycoprotein that confer more efficient transmission and dampen the efficacy of COVID-19 vaccines and antibody therapies. S mediates virus entry and is the primary target for antibody responses, with structural studies of soluble S variants revealing an increased propensity toward conformations accessible to the human angiotensin-converting enzyme 2 (hACE2) receptor. However, real-time observations of conformational dynamics that govern the structural equilibriums of the S variants have been lacking. Here, we report single-molecule Förster resonance energy transfer (smFRET) studies of critical mutations observed in VOCs, including D614G and E484K, in the context of virus particles. Investigated variants predominately occupied more open hACE2-accessible conformations, agreeing with previous structures of soluble trimers. Additionally, these S variants exhibited slower transitions in hACE2-accessible/bound states. Our finding of increased S kinetic stability in the open conformation provides a new perspective on SARS-CoV-2 adaptation to the human population. IMPORTANCE SARS-CoV-2 surface S glycoprotein—the target of antibodies and vaccines—is responsible for binding to the cellular receptor hACE2. The interactions between S and hACE2 trigger structural rearrangements of S from closed to open conformations prerequisite for virus entry. Under the selection pressure imposed by adaptation to the human host and increasing vaccinations and convalescent patients, SARS-CoV-2 is evolving and has adopted numerous mutations on S variants. These promote virus spreading and immune evasion, partially by increasing the propensity of S to adopt receptor-binding competent open conformations. Here, we determined a time dimension, using smFRET to delineate the temporal prevalence of distinct structures of S in the context of virus particles. We present the first experimental evidence of decelerated transition dynamics from the open state, revealing increased stability of S open conformations to be part of the SARS-CoV-2 adaption strategies.

• Publisher: American Society for Microbiology
• Subject: ACE2 / Angiotensin / Angiotensin-converting enzyme 2 / Antibodies / Biological Evolution / Conformation / conformational dynamics / Coronaviruses / COVID-19 / COVID-19 Vaccines / Dyes / Efficiency / Energy transfer / Enzymes / Fluorescence resonance energy transfer / Glycoproteins / HIV / Human immunodeficiency virus / Humans / Immunotherapy / Labeling / Mutation / Pandemics / Peptides / Peptidyl-dipeptidase A / Protein Binding / Protein Conformation / Proteins / Receptors, Virus - metabolism / Research Article / SARS-CoV-2 - genetics / SARS-CoV-2 variants / Severe acute respiratory syndrome coronavirus 2 / single-molecule FRET / spike glycoprotein / Spike Glycoprotein, Coronavirus - metabolism / structure / Vaccines / Virology / Viruses