scholarly journals Emerging SARS-CoV-2 Variants of Concern: Spike Protein Mutational Analysis and Epitope for Broad Neutralization

2021 ◽  
Author(s):  
Dhiraj Mannar ◽  
James W. Saville ◽  
Zehua Sun ◽  
Xing Zhu ◽  
Michelle M. Marti ◽  
...  
Keyword(s):  
Comparative Analysis ◽  
Mutational Analysis ◽  
Antibody Fragment ◽  
Spike Protein ◽  
Structural Rearrangements ◽  
Antibody Neutralization ◽  
Structural Role ◽  
Terminal Domain ◽  
Unique Mode

Mutations in the spike glycoproteins of SARS-CoV-2 variants of concern have independently been shown to enhance aspects of spike protein fitness. Here, we report the discovery of a novel antibody fragment (VH ab6) that neutralizes all major variants, with a unique mode of binding revealed by cryo-EM studies. Further, we provide a comparative analysis of the mutational effects within variant spikes and identify the structural role of mutations within the NTD and RBD in evading antibody neutralization. Our analysis shows that the highly mutated Gamma N-terminal domain exhibits considerable structural rearrangements, partially explaining its decreased neutralization by convalescent sera. Our results provide mechanistic insights into the structural, functional, and antigenic consequences of SARS-CoV-2 spike mutations and highlight a spike protein vulnerability that may be exploited to achieve broad protection against circulating variants.

scholarly journals Oligomerization of Mumps Virus Phosphoprotein

2015 ◽  
Vol 89 (21) ◽  
pp. 11002-11010 ◽  
Author(s):  
Adrian Pickar ◽  
Andrew Elson ◽  
Yang Yang ◽  
Pei Xu ◽  
Ming Luo ◽  
...  
Keyword(s):  
Rna Synthesis ◽  
Mutational Analysis ◽  
Mumps Virus ◽  
Viral Rna ◽  
Large Protein ◽  
Terminal Domain ◽  
P Protein ◽  
Minigenome System ◽  
Oligomerization Domain

ABSTRACTThe mumps virus (MuV) genome encodes a phosphoprotein (P) that is important for viral RNA synthesis. P forms the viral RNA-dependent RNA polymerase with the large protein (L). P also interacts with the viral nucleoprotein (NP) and self-associates to form a homotetramer. The P protein consists of three domains, the N-terminal domain (PN), the oligomerization domain (PO), and the C-terminal domain (PC). While PNis known to relax the NP-bound RNA genome, the roles of POand PCare not clear. In this study, we investigated the roles of POand PCin viral RNA synthesis using mutational analysis and a minigenome system. We found that PNand PCfunctions can betrans-complemented. However, this complementation requires PO, indicating that POis essential for P function. Using thistrans-complementation system, we found that P forms parallel dimers (PNto PNand PCto PC). Furthermore, we found that residues R231, K238, K253, and K260 in POare critical for P's functions. We identified PCto be the domain that interacts with L. These results provide structure-function insights into the role of MuV P.IMPORTANCEMuV, a paramyxovirus, is an important human pathogen. The P protein of MuV is critical for viral RNA synthesis. In this work, we established a novel minigenome system that allows the domains of P to be complemented intrans. Using this system, we confirmed that MuV P forms parallel dimers. An understanding of viral RNA synthesis will allow the design of better vaccines and the development of antivirals.

scholarly journals Structural and Biochemical Rationale for Enhanced Spike Protein Fitness in Delta and Kappa SARS-CoV-2 Variants

2021 ◽  
Author(s):  
James W. Saville ◽  
Dhiraj Mannar ◽  
Xing Zhu ◽  
Shanti S. Srivastava ◽  
Alison M. Berezuk ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Viral Fitness ◽  
Spike Protein ◽  
Wild Type ◽  
Antibody Neutralization ◽  
Vaccination Rates ◽  
Modest Increase ◽  
Terminal Domain ◽  
Cryo Electron Microscopy ◽  
Neutralizing Epitopes

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 novel head-to-head dimer-of-trimers assembly, which we demonstrate is a result of the E484Q mutation. The combination of increased antibody escape and enhanced ACE2 binding provides an explanation, in part, for the rapid global dominance of the Delta variant.

scholarly journals SARS-CoV-2 gained the unique spike protein S1-N-Terminal Domain from the promising pangolins mixing vessel: A novel clue for the pandemic outbreak

2021 ◽  
Author(s):  
Perumal desingu ◽  
K Nagarajan
Keyword(s):  
Selection Pressure ◽  
Neutralizing Antibody ◽  
Spike Protein ◽  
Type I ◽  
The Novel ◽  
Type Ii ◽  
Furin Cleavage ◽  
Terminal Domain ◽  
Furin Cleavage Site

Abstract The clue behind the emergence of SARS-CoV-2 remains a huge debate among the virologist, policymakers, and general public, while the gain-of-function hypothesizes mostly focused on the furin cleavage site and receptor-binding domain (RBD) of the spike (S) protein. Here, we report that the SARS-CoV-2 gained the novel human-specific spike protein S1-N-Terminal Domain (S1-NTD) (Type-I) which is present only in SARS-CoV-2. Interestingly, SARS-CoV-2-rB-CoV showed unique bat-specific Type-II and Type-III-S1-NTD, which is not present in other SARS coronaviruses, including SARS-CoV-2 variants. We also found widespread recombination and selection pressure in the S1-NTDs of the bat viruses. In addition, the Pangolin/GX/2018 and Pangolin/Guangdong/2019 lineages showed close identity (73-79%) with the Type-I-S1-NTD and Type-II-S1-NTD respectively. This justifies that the pangolin is the mixing vessel (intermediate host) to exchange the bat-specific Type-II-S1-NTD in the SARS-CoV-2-rB-CoV into Type-I-like-S1-NTD in pangolin through recombination. Furthermore, the pangolin virus with Type-I-like-S1-NTD jumped into humans which then transformed into SARS-CoV-2 with Type-I-S1-NTD by host selection pressure. Remarkably, we characterized the bat/Cambodia virus as a recombinant SARS-CoV-2/RatG13 with the S1-NTD of bat-SARS-like viruses; while only bat/RatG13 with Type-I-S1-NTD established a huge pandemic outbreak. Additionally, recent SARS-CoV-2 S1-NTD specific neutralizing antibody-based studies support the role of S1-NTD in the post-attachment of the virus; fusion, virus dissemination, and cell-cell fusion thereby prevent the onset of infection; and most of the SARS-CoV-2 variants with increased transmissibility were linked to the S1-NTD mutations. Collectively, our results strongly suggest that the gain of Type-I-S1-NTD in the SARS-CoV-2 is the reason for the pandemic outbreak.

scholarly journals The N-terminal domain of spike glycoprotein mediates SARS-CoV-2 infection by associating with L-SIGN and DC-SIGN

2020 ◽  
Author(s):  
Wai Tuck Soh ◽  
Yafei Liu ◽  
Emi E. Nakayama ◽  
Chikako Ono ◽  
Shiho Torii ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Cell Receptor ◽  
Spike Protein ◽  
Primary Host ◽  
Angiotensin Converting Enzyme 2 ◽  
Lectin Receptor ◽  
Terminal Domain ◽  
Host Cell Receptor ◽  
Protein Serum

The widespread occurrence of SARS-CoV-2 has had a profound effect on society and a vaccine is currently being developed. Angiotensin-converting enzyme 2 (ACE2) is the primary host cell receptor that interacts with the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Although pneumonia is the main symptom in severe cases of SARS-CoV-2 infection, the expression levels of ACE2 in the lung is low, suggesting the presence of another receptor for the spike protein. In order to identify the additional receptors for the spike protein, we screened a receptor for the SARS-CoV-2 spike protein from the lung cDNA library. We cloned L-SIGN as a specific receptor for the N-terminal domain (NTD) of the SARS-CoV-2 spike protein. The RBD of the spike protein did not bind to L-SIGN. In addition, not only L-SIGN but also DC-SIGN, a closely related C-type lectin receptor to L-SIGN, bound to the NTD of the SARS-CoV-2 spike protein. Importantly, cells expressing L-SIGN and DC-SIGN were both infected by SARS-CoV-2. Furthermore, L-SIGN and DC-SIGN induced membrane fusion by associating with the SARS-CoV-2 spike protein. Serum antibodies from infected patients and a patient-derived monoclonal antibody against NTD inhibited SARS-CoV-2 infection of L-SIGN or DC-SIGN expressing cells. Our results highlight the important role of NTD in SARS-CoV-2 dissemination through L-SIGN and DC-SIGN and the significance of having anti-NTD neutralizing antibodies in antibody-based therapeutics.

scholarly journals Inhibition of Protein Synthesis by Y Box-Binding Protein 1 Blocks Oncogenic Cell Transformation

2005 ◽  
Vol 25 (6) ◽  
pp. 2095-2106 ◽  
Author(s):  
Andreas G. Bader ◽  
Peter K. Vogt
Keyword(s):  
Rna Binding ◽  
Mutational Analysis ◽  
Cell Transformation ◽  
Binding Protein ◽  
Pi3k Pathway ◽  
Terminal Domain ◽  
Localization Signal ◽  
Phosphoinositide 3 Kinase ◽  
Mrna Binding

ABSTRACT The multifunctional Y box-binding protein 1 (YB-1) is transcriptionally repressed by the oncogenic phosphoinositide 3-kinase (PI3K) pathway (with P3K as an oncogenic homolog of the catalytic subunit) and, when reexpressed with the retroviral vector RCAS, interferes with P3K- and Akt-induced transformation of chicken embryo fibroblasts. Retrovirally expressed YB-1 binds to the cap of mRNAs and inhibits cap-dependent and cap-independent translation. To determine the requirements for the inhibitory role of YB-1 in P3K-induced transformation, we conducted a mutational analysis, measuring YB-1-induced interference with transformation, subcellular localization, cap binding, mRNA binding, homodimerization, and inhibition of translation. The results show that (i) interference with transformation requires RNA binding and a C-terminal domain that is distinct from the cytoplasmic retention domain, (ii) interference with transformation is tightly correlated with inhibition of translation, and (iii) masking of mRNAs by YB-1 is not sufficient to block transformation or to inhibit translation. We identified a noncanonical nuclear localization signal (NLS) in the C-terminal half of YB-1. A mutant lacking the NLS retains its ability to interfere with transformation, indicating that a nuclear function is not required. These results suggest that YB-1 interferes with P3K-induced transformation by a specific inhibition of translation through its RNA-binding domain and a region in the C-terminal domain. Potential functions of the C-terminal region are discussed.

The Role of the Zakat System during the Colonial-period in Malaysia and Uzbekistan: A Comparative Analysis

2017 ◽  
Vol 04 ◽  
pp. 40-54
Author(s):  
Avazbek Ganiyev Oybekovich ◽  
◽  
Hassan Shakeel Shah ◽  
Mohammad Ayaz ◽  
◽  
...  
Keyword(s):  
Comparative Analysis ◽  
Colonial Period

The role of graining in ensuring food security

2020 ◽  
pp. 75-79
Author(s):  
R. M. Gambarova
Keyword(s):  
Food Security ◽  
Comparative Analysis ◽  
Systems Approach ◽  
Point Of View ◽  
Government Support ◽  
Grain Production ◽  
The Government ◽  
Favorable Conditions ◽  
Grain Farms

Relevance. Grain is the key to strategic products to ensure food security. From this point of view, the creation of large grain farms is a matter for the country's selfsufficiency and it leading to a decrease in financial expense for import. Creation of such farms creates an abundance of productivity from the area and leads to obtaining increased reproductive seeds. The main policy of the government is to minimize dependency from import, create abundance of food and create favorable conditions for export potential.The purpose of the study: the development of grain production in order to ensure food security of the country and strengthen government support for this industry.Methods: comparative analysis, systems approach.Results. As shown in the research, if we pay attention to the activities of private entrepreneurship in the country, we can see result of the implementation of agrarian reforms after which various types of farms have been created in republic.The role of privateentrepreneurshipinthedevelopmentofproduction is great. Тhe article outlines the sowing area, production, productivity, import, export of grain and the level of selfsufficiency in this country from 2015 till 2017.

Russian Museum of Emperor Alexander III as a place of memory

2020 ◽  
Vol 2020 (11-1) ◽  
pp. 132-147
Author(s):  
Dmitry Rakovsky
Keyword(s):  
Comparative Analysis ◽  
Historical Consciousness ◽  
Russian Society ◽  
Museum Collection ◽  
Works Of Art ◽  
History Of ◽  
The Creation ◽  
Historical Representations

The main purpose of this article is to study the role of the Russian Museum in the formation of the historical consciousness of Russian society. In this context, the author examines the history of the creation of the Russian Museum of Emperor Alexander III and its pre-revolutionary collections that became the basis of this famous museum collection (in particular, the composition of the museum’s expositions for 1898 and 1915). Within the framework of the methodology proposed by the author, the works of art presented in the museum’s halls were selected and distributed according to the historical eras that they reflect, and a comparative analysis of changes in the composition of the expositions was also carried out. This approach made it possible to identify the most frequently encountered historical heroes, to consider the representation of their images in the museum’s expositions, and also to provide a systemic reconstruction of historical representations broadcast in its halls.

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