scholarly journals Crystal Structure of Non-Structural Protein 10 from Severe Acute Respiratory Syndrome Coronavirus-2

2020 ◽  
Vol 21 (19) ◽  
pp. 7375 ◽  
Author(s):  
Annika Rogstam ◽  
Maria Nyblom ◽  
Signe Christensen ◽  
Celeste Sele ◽  
Vladimir O. Talibov ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Severe Acute Respiratory Syndrome ◽  
Sequence Similarity ◽  
Economic Consequences ◽  
Structural Protein ◽  
High Sequence Similarity ◽  
Biophysical Characterization ◽  
Global Pandemic ◽  
Rna Capping

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), causing Coronavirus Disease 19 (COVID-19), emerged at the end of 2019 and quickly spread to cause a global pandemic with severe socio-economic consequences. The early sequencing of its RNA genome revealed its high similarity to SARS, likely to have originated from bats. The SARS-CoV-2 non-structural protein 10 (nsp10) displays high sequence similarity with its SARS homologue, which binds to and stimulates the 3′-to-5′ exoribonuclease and the 2′-O-methlytransferase activities of nsps 14 and 16, respectively. Here, we report the biophysical characterization and 1.6 Å resolution structure of the unbound form of nsp10 from SARS-CoV-2 and compare it to the structures of its SARS homologue and the complex-bound form with nsp16 from SARS-CoV-2. The crystal structure and solution behaviour of nsp10 will not only form the basis for understanding the role of SARS-CoV-2 nsp10 as a central player of the viral RNA capping apparatus, but will also serve as a basis for the development of inhibitors of nsp10, interfering with crucial functions of the replication–transcription complex and virus replication.

scholarly journals Integrative multi-omics landscape of non-structural protein 3 of severe acute respiratory syndrome coronaviruses

2021 ◽  
Author(s):  
Ruona Shi ◽  
Zhenhuan Feng ◽  
Xiaofei Zhang
Keyword(s):  
Mass Spectrometry ◽  
Signal Transduction ◽  
Immune Response ◽  
Severe Acute Respiratory Syndrome ◽  
Ribosomal Proteins ◽  
Structural Protein ◽  
Cellular Functions ◽  
Cellular Effects ◽  
Cellular Changes ◽  
Global Pandemic

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is currently a global pandemic. Extensive investigations have been performed to study the clinical and cellular effects of SARS-CoV-2 infection. Mass spectrometry-based proteomics studies have revealed the cellular changes due to the infection and identified a plethora of interactors for all SARS-CoV-2 components, except for the longest non-structural protein 3 (NSP3). Here, we expressed the full-length NSP3 proteins of SARS-CoV and SARS-CoV-2 to investigate their unique and shared functions using multi-omics methods. We conducted interactome, phosphoproteome, ubiquitylome, transcriptome, and proteome analyses of NSP3-expressing cells. We found that NSP3 plays essential roles in cellular functions such as RNA metabolism and immune response such as NF-kB signal transduction. Interestingly, we showed that SARS-CoV-2 NSP3 has both endoplasmic reticulum and mitochondrial localizations. In addition, SARS-CoV-2 NSP3 is more closely related to mitochondrial ribosomal proteins, whereas SARS-CoV NSP3 is related to the cytosolic ribosomal proteins. In summary, our multi-omics studies of NSP3 enhance our understanding of the functions of NSP3 and offer valuable insights for the development of anti-SARS strategies.

scholarly journals Role of RNA Guanine Quadruplexes in Favoring the Dimerization of SARS Unique Domain in Coronaviruses

2020 ◽  
Author(s):  
Cécilia Hognon ◽  
Tom Miclot ◽  
Cristina Garcia Iriepa ◽  
Antonio Francés-Monerris ◽  
Stephanie Grandemange ◽  
...  
Keyword(s):  
Rational Design ◽  
Economic Consequences ◽  
Binding Modes ◽  
Enhanced Sampling ◽  
Present Contribution ◽  
Global Pandemic ◽  
Protein Dimer ◽  
Dynamics Simulations ◽  
Unique Domain

ABSTRACTCoronaviruses may produce severe acute respiratory syndrome (SARS). As a matter of fact, a new SARS-type virus, SARS-CoV-2, is responsible of a global pandemic in 2020 with unprecedented sanitary and economic consequences for most countries. In the present contribution we study, by all-atom equilibrium and enhanced sampling molecular dynamics simulations, the interaction between the SARS Unique Domain and RNA guanine quadruplexes, a process involved in eluding the defensive response of the host thus favoring viral infection of human cells. Our results evidence two stable binding modes involving an interaction site spanning either the protein dimer interface or only one monomer. The free energy profile unequivocally points to the dimer mode as the thermodynamically favored one. The effect of these binding modes in stabilizing the protein dimer was also assessed, being related to its biological role in assisting SARS viruses to bypass the host protective response. This work also constitutes a first step of the possible rational design of efficient therapeutic agents aiming at perturbing the interaction between SARS Unique Domain and guanine quadruplexes, hence enhancing the host defenses against the virus.TOC GRAPHICS

scholarly journals Crystal structure and functional analysis of human C1ORF123

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5377 ◽  
Author(s):  
Siti Nurulnabila A. Rahaman ◽  
Jastina Mat Yusop ◽  
Zeti-Azura Mohamed-Hussein ◽  
Wan Mohd Aizat ◽  
Kok Lian Ho ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Sequence Similarity ◽  
Physiological Role ◽  
Zinc Ion ◽  
Internal Symmetry ◽  
Chromosome 1 ◽  
Zinc Binding ◽  
Binding Motif ◽  
Functional Studies

Proteins of the DUF866 superfamily are exclusively found in eukaryotic cells. A member of the DUF866 superfamily, C1ORF123, is a human protein found in the open reading frame 123 of chromosome 1. The physiological role of C1ORF123 is yet to be determined. The only available protein structure of the DUF866 family shares just 26% sequence similarity and does not contain a zinc binding motif. Here, we present the crystal structure of the recombinant human C1ORF123 protein (rC1ORF123). The structure has a 2-fold internal symmetry dividing the monomeric protein into two mirrored halves that comprise of distinct electrostatic potential. The N-terminal half of rC1ORF123 includes a zinc-binding domain interacting with a zinc ion near to a potential ligand binding cavity. Functional studies of human C1ORF123 and its homologue in the fission yeast Schizosaccharomyces pombe (SpEss1) point to a role of DUF866 protein in mitochondrial oxidative phosphorylation.

scholarly journals The crystal structure of mycobacterial epoxide hydrolase A

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Eike C. Schulz ◽  
Sara R. Henderson ◽  
Boris Illarionov ◽  
Thomas Crosskey ◽  
Stacey M. Southall ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Substrate Specificity ◽  
Drug Targets ◽  
Epoxide Hydrolase ◽  
Sequence Similarity ◽  
Structural Similarity ◽  
High Sequence Similarity ◽  
High Structural Similarity ◽  
Potential Drug Targets ◽  
Insight Into

Abstract The human pathogen Mycobacterium tuberculosis is the causative agent of tuberculosis resulting in over 1 million fatalities every year, despite decades of research into the development of new anti-TB compounds. Unlike most other organisms M. tuberculosis has six putative genes for epoxide hydrolases (EH) of the α/β-hydrolase family with little known about their individual substrates, suggesting functional significance for these genes to the organism. Due to their role in detoxification, M. tuberculosis EH’s have been identified as potential drug targets. Here, we demonstrate epoxide hydrolase activity of M. thermoresistibile epoxide hydrolase A (Mth-EphA) and report its crystal structure in complex with the inhibitor 1,3-diphenylurea at 2.0 Å resolution. Mth-EphA displays high sequence similarity to its orthologue from M. tuberculosis and generally high structural similarity to α/β-hydrolase EHs. The structure of the inhibitor bound complex reveals the geometry of the catalytic residues and the conformation of the inhibitor. Comparison to other EHs from mycobacteria allows insight into the active site plasticity with respect to substrate specificity. We speculate that mycobacterial EHs may have a narrow substrate specificity providing a potential explanation for the genetic repertoire of epoxide hydrolase genes in M. tuberculosis.

scholarly journals A ROLE OF ENVIRONMENTAL FACTORS ON CALCIUM SIGNALING GENES IN NEUROSPORA CRASSA

2015 ◽  
Vol 5 (3) ◽  
pp. 699-710
Author(s):  
Ravi Gedela
Keyword(s):  
Environmental Factors ◽  
Neurospora Crassa ◽  
Nadh Dehydrogenase ◽  
Sequence Similarity ◽  
In Silico Analysis ◽  
High Sequence Similarity ◽  
Multiple Sequence ◽  
Conserve Domain ◽  
Knockout Mutants

 Neurospora crassa possesses a complex of Ca2+_signaling system consisting of 48 Ca2+-signaling proteins.  The Ca+2-signalling  protein plays an important role in a range of processes such as a Ca2+ stress tolerance, hyphal tip branching growth, cytoskeletal organization, cell cycle progression, circadian clocks, sporulation, sexual development, and ultraviolet (uv) survival.  The environmental factors, broadly defined to include chemical, physical, nutritional, and behavioral factors...etc.  In this article, we are reporting here a role of physic-chemical environmental factors pH, glucose and ultraviolet (UV) affect on ∆NCU06366, and ∆NCU05225 Ca2+ -signaling knockout mutants in N. crassa.  The verified result showed that, ∆NCU06366 and ∆NCU05225 Ca2+ -signaling knockout mutants slower growth rate at pH (7.6), and glucose starvation against to the control wild type respectively.  In addition to that the found results showed, ultraviolet (UV) survival, there is no UV radiation affects on ∆NCU06366 and ∆NCU05225 Ca2+-signaling knockout mutants as evaluate to the positive and the negative controls in N.crassa.  Along with that, In-silico analysis Multiple sequence analysis and Phylogenetics tree for conserve domain of NCU05225 (NADH dehydrogenase) and NCU06366 (Ca2+/H+ anti-porter) Ca2+-signaling genes encodes proteins in N.crassa, showed high sequence similarity and 68-100% and 89% homology  to the other class of fungi respectively.  It indicates that, NCU05225 (Mitochondrial NADH dehydrogenase) and NCU06366 (Ca2+/H+ exchangers) Ca2+-signaling gene encoding conserve domain widespread in other class of fungi as well.   

The Role of Gene Conversion in Determining Sequence Variation and Divergence in the Est-5 Gene Family in Drosophila pseudoobscura

Genetics ◽  
1998 ◽  
Vol 148 (1) ◽  
pp. 305-315
Author(s):  
Lynn Mertens King
Keyword(s):  
Gene Family ◽  
Gene Conversion ◽  
Sequence Variation ◽  
Sequence Similarity ◽  
Drosophila Pseudoobscura ◽  
High Sequence Similarity ◽  
Tests Of Neutrality ◽  
Synonymous Sites ◽  
Interspecific Comparisons

Abstract Nucleotide sequences of eight Est-5A and Est-5C genes corresponding to previously sequenced Est-5B genes in Drosophila pseudoobscura were determined to compare patterns of polymorphism and divergence among members of this small gene family. The three esterase genes were also sequenced from D. persimilis and D. miranda for interspecific comparisons. The data provide evidence that gene conversion between loci contributes to polymorphism and to the homogenization of the Est-5 genes. For Est-5B, which encodes one of the most highly polymorphic proteins in Drosophila, 12% of the segregating amino acid variants appear to have been introduced via gene conversion from other members of the gene family. Interlocus gene conversion can also explain high sequence similarity, especially at synonymous sites, between Est-5B and Est-5A. Tests of neutrality using interspecific comparisons show that levels of polymorphism conform to neutral expectations at each Est-5 locus. However, McDonald-Kreitman tests based on intraspecific gene comparisons indicate that positive selection on amino acids has accompanied Est-5 gene duplication and divergence in D. pseudoobscura.

scholarly journals Structure and Function of Filamin C in the Muscle Z-Disc

2020 ◽  
Vol 21 (8) ◽  
pp. 2696 ◽  
Author(s):  
Zhenfeng Mao ◽  
Fumihiko Nakamura
Keyword(s):  
Sequence Similarity ◽  
Actin Binding ◽  
Amino Acid Residues ◽  
Filamin A ◽  
Dimerization Domain ◽  
High Sequence Similarity ◽  
Actin Binding Domain ◽  
And Function ◽  
Filamin C

Filamin C (FLNC) is one of three filamin proteins (Filamin A (FLNA), Filamin B (FLNB), and FLNC) that cross-link actin filaments and interact with numerous binding partners. FLNC consists of a N-terminal actin-binding domain followed by 24 immunoglobulin-like repeats with two intervening calpain-sensitive hinges separating R15 and R16 (hinge 1) and R23 and R24 (hinge-2). The FLNC subunit is dimerized through R24 and calpain cleaves off the dimerization domain to regulate mobility of the FLNC subunit. FLNC is localized in the Z-disc due to the unique insertion of 82 amino acid residues in repeat 20 and necessary for normal Z-disc formation that connect sarcomeres. Since phosphorylation of FLNC by PKC diminishes the calpain sensitivity, assembly, and disassembly of the Z-disc may be regulated by phosphorylation of FLNC. Mutations of FLNC result in cardiomyopathy and muscle weakness. Although this review will focus on the current understanding of FLNC structure and functions in muscle, we will also discuss other filamins because they share high sequence similarity and are better characterized. We will also discuss a possible role of FLNC as a mechanosensor during muscle contraction.

scholarly journals Detailed Analyses of the Expression Patterns of Potential Severe Acute Respiratory Syndrome Coronavirus 2 Receptors in the Human Heart Using Single-Nucleus RNA Sequencing

2021 ◽  
Vol 8 ◽  
Author(s):  
Jie Ren ◽  
Yuze Zhang ◽  
Shishi Liu ◽  
Xiangjie Li ◽  
Xiaogang Sun
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Human Heart ◽  
Sequence Similarity ◽  
Expression Patterns ◽  
Cardiac Injury ◽  
Cell Types ◽  
Cardiovascular Complications ◽  
High Sequence Similarity ◽  
Ventricular Cells ◽  
Single Nucleus

Cardiac injury is a common complication of coronavirus disease 2019 (COVID-19), but the exact mechanisms have not been completely elucidated. The virus receptors on subsets of cells are key determinants of susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Due to its high sequence similarity to SARS-CoV, SARS-CoV-2 also utilizes ACE2 as the cell entry receptor. A growing number of studies have indicated that other receptors apart from ACE2 are involved in SARS-CoV-2 infection. This study aimed to elucidate the expression characteristics of SARS-CoV-2 cellular receptors in the heart. We first investigated ACE2 expression in a comprehensive transcriptional landscape of the human heart comprising single-nucleus RNA-seq (snRNA-seq) data for >280,000 cells. Then, the expression distributions of novel SARS-CoV-2 receptors were analyzed at the single-cell level to clarify the cardiovascular complications in COVID-19. We observed a higher percentage of ACE2-positive cells in pericytes (8.3%), fibroblasts (5.1%), and adipocytes (4.4%) in the human heart, compared to other cell types. The frequency of ACE2-positive cells in each cell type from the ventricles was significantly higher than that in the atria, suggesting that the ventricular cells are more susceptible to SARS-CoV-2 infection. The distribution patterns of other receptors (BSG, HSPA5, KREMEN1, NRP1, ANPEP, AXL) were significantly different from those of ACE2, demonstrating higher expression levels in ventricular cardiomyocytes. Moreover, our results suggest that fibroblasts and adipocytes, aside from pericytes, may be vulnerable targets for SARS-CoV-2 infection in the human heart. Our study presents potential targets for future clinical studies and interventions for cardiac injury in patients with COVID-19.

scholarly journals Focus on the Potential Role of Lung Ultrasound in COVID-19 Pandemic: What More to Do?

2020 ◽  
Vol 17 (22) ◽  
pp. 8398
Author(s):  
Beatrice Ragnoli ◽  
Mario Malerba
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Potential Role ◽  
Lung Ultrasound ◽  
Hubei Province ◽  
Global Pandemic ◽  
The World

COVID-19, a novel severe acute respiratory syndrome (SARS) emerging in China’s Hubei province in late 2019, due to a new coronavirus (SARS-CoV-2), is causing a global pandemic involving many areas of the world, which so far counts more than 43 million cases and more than 1,155,000 deaths worldwide [...]

scholarly journals Gastrointestinal Microenvironment and the Gut-Lung Axis in the Immune Responses of Severe COVID-19

2021 ◽  
Vol 8 ◽  
Author(s):  
Yun Yang ◽  
Weishan Huang ◽  
Yubo Fan ◽  
Guo-Qiang Chen
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Immune Responses ◽  
Alternative Medicine ◽  
Human Health ◽  
High Frequency ◽  
Therapeutic Potential ◽  
Close Association ◽  
Current Evidence ◽  
Global Pandemic

The global pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an unprecedented threat to the human health. A close association of the digestive tract is implied by the high frequency of gastrointestinal syndromes among COVID-19 patients. A better understanding of the role of intestinal microenvironment in COVID-19 immunopathology will be helpful to improve the control of COVID-19 associated morbidity and mortality. This review summarizes the immune responses associated with the severity of COVID-19, the current evidence of SARS-CoV-2 intestinal tropism, and the potential involvement of gut microenvironment in COVID-19 severity. Additionally, we discuss the therapeutic potential of probiotics as an alternative medicine to prevent or alleviate severe COVID-19 outcome.

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