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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinE (146)

ProteinS (40)

ProteinN (33)

ComplexRdRp (17)

ProteinM (17)


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SARS-CoV-2 Proteins
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    Self-collected oral, nasal and saliva samples yield sensitivity comparable to professional-collected oro-nasopharyngeal swabs in SARS-CoV-2 diagnosis

    Authors: Maximilian Gertler; Eva Krause; Welmoed van Loon; Niklas Krug; Franka Kausch; Chiara Rohardt; Heike Roessig; Janine Michel; Andreas Nitsche; Marcus A. Mall; Olga Nikolai; Franziska Hommes; Susen Burock; Andreas K. Lindner; Frank P. Mockenhaupt; Ulrich Pison; Joachim Seybold

    doi:10.1101/2021.04.13.21255345 Date: 2021-04-20 Source: medRxiv

    Introduction: Containment of the COVID-19 pandemic MESHD requires broad-scale testing. Laboratory capacities for real-time-PCR were increased, and are complemented by Ag-tests. However, sample-collection still requires qualified personnel and protective equipement, may produce transmission to others during conduct and travel, and is perceived uncomfortable. We tested sensitivity of three simplified self-sampling techniques compared to professional-collected combined oro-nasopharyngeal samples ( cOP HGNC/NP). Methods: From 62 symptomatic COVID-19 MESHD outpatients, we obtained simultaneously three self- and one professional-collected sample after initial confirmation in a testing centre: (i) combination swab (tongue, cheek, both nasal vestibula, MS, (ii) saliva sponge combined with both nasal vestibula, SN, and (iii) gargled tap water, GW, (iv) professionally-collected cOP HGNC/NP (standard). We compared the results of SARS-CoV-2 PCR-assays detecting E-gene PROTEIN and ORF1ab PROTEIN for the different sample types and performed bivariate statistical analysis to determine the variables reducing sensitivity of the self-collecting procedures. Results: SARS-CoV-2 RNA was detected in all 62 professionally-collected cOP HGNC/NP. MS and SN samples showed a sensitivity of 95.2% (95%CI 86.5-99.0) and GW samples of 88.7% (78.1-95.3). Compared to the median ct-values of cOP HGNC/NP samples for E-gene PROTEIN (20.7) and ORF1ab PROTEIN (20.2) these were higher for MS (22.6 and 21.8), SN (23.3 and 22.3), and for GW (30.3 and 29.8). For MS and SN samples but not for GW specimens, false negativity in bivariate analysis was associated with non-German mother-tongue, number of sampling errors, and with symptom duration. For symptom duration of [≤]8 days, test sensitivity for SN samples was 98.2% (95%CI 90.4-100.0) and for MS 96.4% (95%CI 87.7-99.6) and drops after day 8 below 90%. Discussion: The study is limited to sensitivity of self-collection in symptomatic patients. Still, in this group, self-collected oral/nasal/saliva samples are reliable alternatives to professional-collected cOP HGNC/NP samples, if symptom duration does not exceed eight days and operational errors are minimized. Self-sampling could contribute to up-scaling of safe and efficient testing.

    The SARS CoV-1 3a protein disrupts Golgi complex morphology and cargo trafficking

    Authors: Rex R. Gonzales; Carolyn E. Machamer

    doi:10.1101/2021.04.19.440492 Date: 2021-04-19 Source: bioRxiv

    Coronaviruses assemble by budding into the endoplasmic reticulum-Golgi intermediate compartment, but the pathway of egress from infected cells is not well understood. Efficient egress of infectious bronchitis virus MESHD (a gamma coronavirus, CoV) requires neutralization of Golgi pH by the envelope (E) protein PROTEIN. This results in reduced rates of cargo traffic and disrupts Golgi morphology, but it protects the spike protein PROTEIN from aberrant proteolysis. The severe acute respiratory syndrome MESHD (SARS) CoV-1 E protein PROTEIN does not disrupt the Golgi, however. We show here that in transfected cells, the ORF3a PROTEIN protein of SARS CoV-1 disrupts Golgi morphology, cargo trafficking and luminal pH. Unlike the infectious bronchitis MESHD virus E protein PROTEIN, these functions of the SARS CoV-1 3a protein appear to require its viroporin activity. Thus, neutralization of acidic compartments may be a universal feature of CoV infection MESHD, although different viral proteins and mechanisms may be used to achieve this outcome.

    Genome-wide CRISPR activation screen identifies novel receptors for SARS-CoV-2 entry MESHD

    Authors: Shiyou Zhu; Ying Liu; Zhuo Zhou; Zhiying Zhang; Xia Xiao; Zhiheng Liu; Ang Chen; Xiaojing Dong; Feng Tian; Shihua Chen; Yiyuan Xu; Chunhui Wang; Qiheng Li; Xuran Niu; Qian Pan; Shuo Du; Junyu Xiao; Jianwei Wang; Wensheng Wei

    doi:10.1101/2021.04.08.438924 Date: 2021-04-09 Source: bioRxiv

    The ongoing pandemic of coronavirus disease 2019 MESHD ( COVID-19 MESHD) caused by severe acute respiratory syndrome coronavirus 2 MESHD (SARS-CoV-2) has been endangering worldwide public health and economy. SARS-CoV-2 infects MESHD a variety of tissues where the known receptor ACE2 HGNC is low or almost absent, suggesting the existence of alternative pathways for virus entry. Here, we performed a genome-wide barcoded-CRISPRa screen to identify novel host factors that enable SARS-CoV-2 infection MESHD. In addition to known host proteins, i.e PROTEIN. ACE2 HGNC, TMPRSS2 HGNC, and NRP1 HGNC, we identified multiple host components, among which LDLRAD3 HGNC, TMEM30A HGNC, and CLEC4G HGNC were confirmed as functional receptors for SARS-CoV-2. All these membrane proteins bind directly to spike's N-terminal domain ( NTD HGNC). Their essential and physiological roles have all been confirmed in either neuron or liver cells. In particular, LDLRAD3 HGNC and CLEC4G HGNC mediate SARS-CoV-2 entry MESHD and infection in a fashion independent of ACE2 HGNC. The identification of the novel receptors and entry mechanisms could advance our understanding of the multiorgan tropism of SARS-CoV-2, and may shed light on the development of the therapeutic countermeasures against COVID-19 MESHD.

    Interactions of SARS-CoV-2 envelope protein PROTEIN with amilorides correlate with antiviral activity

    Authors: Sang Ho Park; Haley Siddiqi; Daniela Castro; Anna De Angelis; Aaron L. Oom; Charlotte Stoneham; Mary Lewinski; Alex Clark; Ben Croker; Aaron Carlin; John Guatelli; Stanley J. Opella

    doi:10.1101/2021.04.06.438579 Date: 2021-04-06 Source: bioRxiv

    SARS-CoV-2 is the novel coronavirus that is the causative agent of COVID-19 MESHD, a sometimes-lethal respiratory infection MESHD responsible for a world-wide pandemic. The envelope (E) protein PROTEIN, one of four structural proteins encoded in the viral genome, is a 75-residue integral membrane protein whose transmembrane domain exhibits ion channel activity and whose cytoplasmic domain participates in protein-protein interactions. These activities contribute to several aspects of the viral replication-cycle, including virion assembly, budding, release, and pathogenesis. Here, we describe the structure and dynamics of full-length SARS-CoV-2 E protein PROTEIN in hexadecylphosphocholine micelles by NMR spectroscopy. We also characterized its interactions with four putative ion channel inhibitors. The chemical shift index and dipolar wave plots establish that E protein PROTEIN consists of a long transmembrane helix (residues 8-43) and a short cytoplasmic helix (residues 53-60) connected by a complex linker that exhibits some internal mobility. The conformations of the N-terminal transmembrane domain and the C-terminal cytoplasmic domain are unaffected by truncation from the intact protein. The chemical shift perturbations of E protein PROTEIN spectra induced by the addition of the inhibitors demonstrate that the N-terminal region (residues 6-18) is the principal binding site. The binding affinity of the inhibitors to E protein PROTEIN in micelles correlates with their antiviral potency in Vero E6 cells: HMA {approx} EIPA > DMA >> Amiloride, suggesting that bulky hydrophobic groups in the 5 position of the amiloride pyrazine ring play essential roles in binding to E protein PROTEIN and in antiviral activity. An N15A mutation increased the production of virus-like particles, induced significant chemical shift changes from residues in the inhibitor binding site, and abolished HMA binding, suggesting that Asn15 plays a key role in maintaining the protein conformation near the binding site. These studies provide the foundation for complete structure determination of E protein PROTEIN and for structure-based drug discovery targeting this protein. Author SummaryThe novel coronavirus SARS-CoV-2, the causative agent of the world-wide pandemic of COVID-19 MESHD, has become one of the greatest threats to human health. While rapid progress has been made in the development of vaccines, drug discovery has lagged, partly due to the lack of atomic-resolution structures of the free and drug-bound forms of the viral proteins. The SARS-CoV-2 envelope (E) protein PROTEIN, with its multiple activities that contribute to viral replication, is widely regarded as a potential target for COVID-19 MESHD treatment. As structural information is essential for drug discovery, we established an efficient sample preparation system for biochemical and structural studies of intact full-length SARS-CoV-2 E protein PROTEIN and characterized its structure and dynamics. We also characterized the interactions of amilorides with specific E protein PROTEIN residues and correlated this with their antiviral activity during viral replication. The binding affinity of the amilorides to E protein PROTEIN correlated with their antiviral potency, suggesting that E protein PROTEIN is indeed the likely target of their antiviral activity. We found that residue asparagine15 plays an important role in maintaining the conformation of the amiloride binding site, providing molecular guidance for the design of inhibitors targeting E protein PROTEIN.

    Altered O-glycosylation Level of SARS-CoV-2 Spike MESHD SARS-CoV-2 Spike PROTEIN Protein by Host O-glycosyltransferase Strengthens Its Trimeric Structure

    Authors: Zhijue Xu; Xin Ku; Jiaqi Tian; Han Zhang; Jingli Hou; Can Zhang; Jingjing Shi; Yang Li; Hiroyuki Kaji; Sheng-ce Tao; Atsushi Kuno; Wei Yan; Lin-Tai Da; Yan Zhang

    doi:10.1101/2021.04.06.438614 Date: 2021-04-06 Source: bioRxiv

    The trimeric spike protein (S PROTEIN) mediates host-cell entry and membrane fusion of SARS-CoV-2. S protein PROTEIN is highly glycosylated, whereas its O-glycosylation is still poorly understood. Herein, we site-specifically examine the O-glycosylation of S protein PROTEIN through a mass spectrometric approach with HCD MESHD-triggered-ETD model. We identify 15 high-confidence O-glycosites and at least 10 distinct O-glycan structures on S protein PROTEIN. Peptide microarray assays prove that human ppGalNAc-T6 actively participates in O-glycosylation of S protein PROTEIN. Importantly, the upregulation of ppGalNAc-T6 expression can profoundly enhance the O-glycosylation level by generating new O-glycosites and increasing both O-glycan heterogeneity and intensities. Further molecular dynamics simulations reveal that the O-glycosylation on the protomer-interface regions, which are mainly modified by ppGalNAc-T6, can potentially stabilize the trimeric S protein PROTEIN structure. Our work provides deep molecular insights of how viral infection harnesses the host O-glycosyltransferases MESHD to dynamically regulate the O-glycosylation level of the viral envelope protein PROTEIN responsible for membrane fusion.

    Monitoring occurrence of SARS-CoV-2 in school populations: a wastewater-based approach

    Authors: Victor Castro Gutierrez; Francis Hassard; Milan Vu; Rodrigo Leitao; Beata Burczynska; Dirk Wildeboer; Isobel Stanton; Shadi Rahimzadeh; Gianluca Baio; Hemda Garelick; Jan Hofman; Barbara Kasprzyk-Hordern; Rachel Kwiatkowska; Azeem Majeed; Sally Priest; Jasmine Grimsley; Lian Lundy; Andrew C Singer; Mariachiara Di Cesare

    doi:10.1101/2021.03.25.21254231 Date: 2021-03-26 Source: medRxiv

    Clinical testing of children in schools is challenging, with economic implications limiting its frequent use as a monitoring tool of the risks assumed by children and staff during the COVID-19 pandemic MESHD. Here, a wastewater based epidemiology approach has been used to monitor 16 schools (10 primary, 5 secondary and 1 post-16 and further education for a total of 17 sites) in England. A total of 296 samples over 9 weeks have been analysed for N1 and E genes PROTEIN using qPCR methods. Of the samples returned, 47.3% were positive for one or both genes with a frequency of detection in line with the respective community. WBE offers a promising low cost, non-invasive approach for supplementing clinical testing and can offer longitudinal insights that are impractical with traditional clinical testing.

    S-acylation controls SARS-Cov-2 membrane lipid organization and enhances infectivity MESHD

    Authors: Francisco Sarmento Mesquita; Laurence Abrami; Oksana Sergeeva; Priscilla Turelli; Beatrice Kunz; Charlene Raclot; Jonathan Paz Montoya; Luciano Abriata; Matteo Dal Peraro; Didier Trono; F. Gisou van der Goot

    doi:10.1101/2021.03.14.435299 Date: 2021-03-15 Source: bioRxiv

    SARS-CoV-2 virions are surrounded by a lipid bilayer which contains membrane proteins such as Spike PROTEIN, responsible for target-cell binding and virus fusion, the envelope protein E PROTEIN and the accessory protein Orf3a PROTEIN. Here, we show that during SARS-CoV-2 infection MESHD, all three proteins become lipid modified, through action of the S- acyltransferase ZDHHC20 HGNC. Particularly striking is the rapid acylation of Spike on 10 cytosolic cysteines within the ER and Golgi. Using a combination of computational, lipidomics and biochemical approaches, we show that this massive lipidation controls Spike biogenesis and degradation, and drives the formation of localized ordered cholesterol and sphingolipid rich lipid nanodomains, in the early Golgi where viral budding occurs. ZDHHC20 HGNC-mediated acylation allows the formation of viruses with enhanced fusion capacity and overall infectivity. Our study points towards S-acylating enzymes and lipid biosynthesis enzymes as novel therapeutic anti-viral targets.

    Emerging variants of concern in SARS-CoV-2 membrane protein: a highly conserved target with potential pathological and therapeutic implications

    Authors:

    doi:10.1101/2021.03.11.434758 Date: 2021-03-11 Source: bioRxiv

    Mutations in the SARS-CoV-2 Membrane (M) gene are relatively uncommon. The M gene encodes the most abundant viral structural protein, and is implicated in multiple viral functions, including initial attachment to the host cell via heparin sulfate proteoglycan, viral protein assembly in conjunction with the N and E genes PROTEIN, and enhanced glucose transport. We have identified a recent spike in the frequency of reported SARS-CoV-2 genomes carrying M gene mutations. This is associated with emergence of a new sub-B.1 clade defined by the previously unreported M:I82T mutation within TM3 HGNC, the third of three membrane spanning helices implicated in glucose transport. The frequency of this mutation increased in the USA from 0.014% in October 2020 to 1.62% in February 2021, a 116-fold change. While constituting 0.7% of the isolates overall, M:I82T sub-B.1 lineage accounted for 14.4% of B.1 lineage isolates in February 2021, similar to the rapid initial increase previously seen with the B.1.1.7 and B.1.429 lineages, which quickly became the dominant lineages in Europe and California over a period of several months. A similar increase in incidence was also noted in another related mutation, V70L, also within the TM2 transmembrane helix. The rapid emergence of this sub-B.1 clade with recurrent I82T mutation suggests that this M gene mutation is more biologically fit, perhaps related to glucose uptake during viral replication, and should be included in ongoing genomic surveillance efforts and warrants further evaluation for potentially increased pathogenic and therapeutic implications.

    Structure and dynamics of the SARS-CoV-2 envelope protein PROTEIN monomer

    Authors: Alexander Kuzmin; Philipp Orekhov; Roman Astashkin; Valentin Gordeliy; Ivan Gushchin

    doi:10.1101/2021.03.10.434722 Date: 2021-03-10 Source: bioRxiv

    Coronaviruses, especially SARS-CoV-2, present an ongoing threat for human wellbeing. Consequently, elucidation of molecular determinants of their function and interaction with host is an important task. Whereas some of the coronaviral proteins are extensively characterized, others remain understudied. Here, we use molecular dynamics simulations to analyze the structure and dynamics of the SARS-CoV-2 envelope protein (E PROTEIN protein, a viroporin) in the monomeric form. The protein consists of three parts: hydrophobic -helical transmembrane domain (TMD) and amphiphilic -helices H2 and H3, which are connected by flexible linkers. We show that TMD is tilted in the membrane, with phenylalanines Phe20, Phe23 and Phe26 facing the lumen. H2 and H3 reside at the membrane surface. Orientation of H2 is not affected by glycosylation, but strongly influenced by palmitoylation pattern of cysteines Cys40, Cys43 and Cys44. On the other hand, glycosylation affects the orientation of H3 and prevents its stacking with H2. We also find that the E protein PROTEIN both generates and senses the membrane curvature, preferably localizing with the cytoplasmic part at the convex regions of the membrane. Curvature sensing may be favorable for assembly of the E protein PROTEIN oligomers, whereas induction of curvature may facilitate budding of the viral particles. The presented results may be helpful for better understanding of the function of coronaviral E protein PROTEIN and viroporins in general, and for overcoming the ongoing SARS-CoV-2 pandemic.

    Comparative studies of the seven human coronavirus envelope proteins PROTEIN using topology prediction and molecular modelling to understand their pathogenicity

    Authors: Dewald Schoeman; Ruben Cloete; Burtram Fielding

    doi:10.1101/2021.03.08.434384 Date: 2021-03-08 Source: bioRxiv

    Human (h) coronaviruses (CoVs) 229E, NL63, OC43, and HKU1 are less virulent and cause mild, self-limiting respiratory tract infections, while SARS-CoV MESHD, MERS-CoV, and SARS-CoV-2, are more virulent and have caused severe outbreaks. The CoV envelope (E) protein PROTEIN, an important contributor to the pathogenesis of severe hCoVs infections MESHD, may provide insight into this disparate severity of the disease. Topology prediction programs and 3D modelling software was used to predict and visualize structural aspects of the hCoV E protein PROTEIN related to its functions. All seven hCoV E proteins PROTEIN largely adopted different topologies, with some distinction between the more virulent and less virulent ones. The 3D models refined this distinction, showing the PDZ-binding motif (PBM) of SARS-CoV MESHD, MERS-CoV, and SARS-CoV-2 to be more flexible than the PBM of hCoVs 229E, NL63, OC43, and HKU1. We speculate that the increased flexibility of the PBM may provide the more virulent hCoVs with a greater degree of freedom, which can allow them to bind to different host proteins and can contribute to a more severe form of the disease. This is the first paper to predict the topologies and model 3D structures of all seven hCoVs E proteins PROTEIN, providing novel insights for possible drug and/or vaccine development.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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