tetano
Editor, Senior Moderator
mBio
. 2022 Feb 15;e0322721.
doi: 10.1128/mbio.03227-21. Online ahead of print.
SARS-CoV-2 Variants Increase Kinetic Stability of Open Spike Conformations as an Evolutionary Strategy
Ziwei Yang[SUP] #[/SUP][SUP] 1 [/SUP], Yang Han[SUP] #[/SUP][SUP] 2 [/SUP], Shilei Ding[SUP] 3 [/SUP], Wei Shi[SUP] 4 [/SUP], Tongqing Zhou[SUP] 4 [/SUP], Andrés Finzi[SUP] 3 [/SUP], Peter D Kwong[SUP] 4 [/SUP], Walther Mothes[SUP] 1 [/SUP], Maolin Lu[SUP] 2 [/SUP]
Affiliations
Abstract
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.
Keywords: SARS-CoV-2 variants; conformational dynamics; single-molecule FRET; spike glycoprotein; structure.
. 2022 Feb 15;e0322721.
doi: 10.1128/mbio.03227-21. Online ahead of print.
SARS-CoV-2 Variants Increase Kinetic Stability of Open Spike Conformations as an Evolutionary Strategy
Ziwei Yang[SUP] #[/SUP][SUP] 1 [/SUP], Yang Han[SUP] #[/SUP][SUP] 2 [/SUP], Shilei Ding[SUP] 3 [/SUP], Wei Shi[SUP] 4 [/SUP], Tongqing Zhou[SUP] 4 [/SUP], Andrés Finzi[SUP] 3 [/SUP], Peter D Kwong[SUP] 4 [/SUP], Walther Mothes[SUP] 1 [/SUP], Maolin Lu[SUP] 2 [/SUP]
Affiliations
- PMID: 35164561
- DOI: 10.1128/mbio.03227-21
Abstract
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.
Keywords: SARS-CoV-2 variants; conformational dynamics; single-molecule FRET; spike glycoprotein; structure.