Structural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants
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Abstract
The Delta and Kappa variants of SARS-CoV-2 co-emerged in India in late 2020, with the Delta variant underlying the resurgence of COVID-19, even in countries with high vaccination rates. In this study, we assess structural and biochemical aspects of viral fitness for these two variants using cryo-electron microscopy (cryo-EM), ACE2-binding and antibody neutralization analyses. Both variants demonstrate escape of antibodies targeting the N-terminal domain, an important immune hotspot for neutralizing epitopes. Compared to wild-type and Kappa lineages, Delta variant spike proteins show modest increase in ACE2 affinity, likely due to enhanced electrostatic complementarity at the RBD-ACE2 interface, which we characterize by cryo-EM. Unexpectedly, Kappa variant spike trimers form a structural head-to-head dimer-of-trimers assembly, which we demonstrate is a result of the E484Q mutation and with unknown biological implications. The combination of increased antibody escape and enhanced ACE2 binding provides an explanation, in part, for the rapid global dominance of the Delta variant.
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SciScore for 10.1101/2021.09.02.458774: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Variant pseudotyped retroviral particles were produced in HEK293T cells as described previously49. HEK293Tsuggested: NoneExpi293 cells were transfected at a density of 3 × 10^6 cells/mL using linear polyethylenimine (Polysciences Cat# 23966-1). Expi293suggested: RRID:CVCL_D615)Recombinant DNA Sentences Resources Antibodies: Recombinant proteins: Cell lines: Recombinant DNA and Oligonucleotides: Software and Algorithms: Pseudovirus Neutralization Assay: SARS-CoV-2 S … SciScore for 10.1101/2021.09.02.458774: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Variant pseudotyped retroviral particles were produced in HEK293T cells as described previously49. HEK293Tsuggested: NoneExpi293 cells were transfected at a density of 3 × 10^6 cells/mL using linear polyethylenimine (Polysciences Cat# 23966-1). Expi293suggested: RRID:CVCL_D615)Recombinant DNA Sentences Resources Antibodies: Recombinant proteins: Cell lines: Recombinant DNA and Oligonucleotides: Software and Algorithms: Pseudovirus Neutralization Assay: SARS-CoV-2 S protein Delta and Kappa genes were synthesized and inserted into pcDNA3.1 ( pcDNA3.1suggested: RRID:Addgene_79663)Expression and Purification of Recombinant Spike Protein Constructs: The wild-type SARS-CoV-2 S HexaPro expression plasmid was previously described44 and was a gift from Jason McLellan (Addgene plasmid #154754; http://n2t.net/addgene:154754; RRID:Addgene_154754). detected: RRID:Addgene_154754)Software and Algorithms Sentences Resources In general, all data processing was performed in cryoSPARC v. cryoSPARCsuggested: (cryoSPARC, RRID:SCR_016501)0.9.352, followed by iterative rounds of refinement in COOT and Phenix v.1.1953. Phenixsuggested: (Phenix, RRID:SCR_014224)Glycans were added at N-linked glycosylation sites in COOT. COOTsuggested: (Coot, RRID:SCR_014222)Figures were prepared using UCSF Chimera, UCSF ChimeraX v.1.1.155, and PyMOL (v.2.2 Schrodinger, LLC) PyMOLsuggested: (PyMOL, RRID:SCR_000305)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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