Plasticity in structure and assembly of SARS-CoV-2 nucleocapsid protein
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Abstract
Worldwide SARS-CoV-2 sequencing efforts track emerging mutations in its spike protein, as well as characteristic mutations in other viral proteins. Besides their epidemiological importance, the observed SARS-CoV-2 sequences present an ensemble of viable protein variants, and thereby a source of information on viral protein structure and function. Charting the mutational landscape of the nucleocapsid (N) protein that facilitates viral assembly, we observe variability exceeding that of the spike protein, with more than 86% of residues that can be substituted, on average by three to four different amino acids. However, mutations exhibit an uneven distribution that tracks known structural features but also reveals highly protected stretches of unknown function. One of these conserved regions is in the central disordered linker proximal to the N-G215C mutation that has become dominant in the Delta variant, outcompeting G215 variants without further spike or N-protein substitutions. Structural models suggest that the G215C mutation stabilizes conserved transient helices in the disordered linker serving as protein–protein interaction interfaces. Comparing Delta variant N-protein to its ancestral version in biophysical experiments, we find a significantly more compact and less disordered structure. N-G215C exhibits substantially stronger self-association, shifting the unliganded protein from a dimeric to a tetrameric oligomeric state, which leads to enhanced coassembly with nucleic acids. This suggests that the sequence variability of N-protein is mirrored by high plasticity of N-protein biophysical properties, which we hypothesize can be exploited by SARS-CoV-2 to achieve greater efficiency of viral assembly, and thereby enhanced infectivity.
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SciScore for 10.1101/2022.02.08.479556: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Recombinant DNA Sentences Resources Protein and oligonucleotides: SARS-CoV-2 nucleocapsid protein # YP_009724397 with quadruple D63G, R203M, G215C, and D377Y mutations including 6His with TEV cleavage site was synthesized and cloned into the pET-29a(+) expression vector by GenScript (Pisctaway, NJ). pET-29a(+ )suggested: NoneSoftware and Algorithms Sentences Resources Alignment of SARS and related sequences was carried out with COBALT at NLM (69), and highlights for similar residues were taken from ESPript (70), plotted with MATLAB (Natick, MATLABsuggested: (MATLAB, RRID:SCR_001622)Results from OddPub: Thank you for sharing your data.
Res…SciScore for 10.1101/2022.02.08.479556: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Recombinant DNA Sentences Resources Protein and oligonucleotides: SARS-CoV-2 nucleocapsid protein # YP_009724397 with quadruple D63G, R203M, G215C, and D377Y mutations including 6His with TEV cleavage site was synthesized and cloned into the pET-29a(+) expression vector by GenScript (Pisctaway, NJ). pET-29a(+ )suggested: NoneSoftware and Algorithms Sentences Resources Alignment of SARS and related sequences was carried out with COBALT at NLM (69), and highlights for similar residues were taken from ESPript (70), plotted with MATLAB (Natick, MATLABsuggested: (MATLAB, RRID:SCR_001622)Results from OddPub: Thank you for sharing your data.
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: Please consider improving the rainbow (“jet”) colormap(s) used on pages 37, 29 and 30. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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