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Plasticity in structure and assembly of SARS-CoV-2 nucleocapsid protein.
Zhao, Huaying; Nguyen, Ai; Wu, Di; Li, Yan; Hassan, Sergio A; Chen, Jiji; Shroff, Hari; Piszczek, Grzegorz; Schuck, Peter.
  • Zhao H; Laboratory of Dynamics of Macromolecular Assembly, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892, USA.
  • Nguyen A; Laboratory of Dynamics of Macromolecular Assembly, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892, USA.
  • Wu D; Biophysics Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Li Y; Proteomics Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
  • Hassan SA; Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  • Chen J; Advanced Imaging and Microscopy Resource, National Institutes of Health, Bethesda, MD 20892, USA.
  • Shroff H; Advanced Imaging and Microscopy Resource, National Institutes of Health, Bethesda, MD 20892, USA.
  • Piszczek G; Biophysics Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Schuck P; Laboratory of Dynamics of Macromolecular Assembly, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892, USA.
PNAS Nexus ; 1(2): pgac049, 2022 May.
Article in English | MEDLINE | ID: covidwho-2237565
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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Full text: Available Collection: International databases Database: MEDLINE Topics: Variants Language: English Journal: PNAS Nexus Year: 2022 Document Type: Article Affiliation country: Pnasnexus

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Full text: Available Collection: International databases Database: MEDLINE Topics: Variants Language: English Journal: PNAS Nexus Year: 2022 Document Type: Article Affiliation country: Pnasnexus