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MeSH Disease

HGNC Genes

SARS-CoV-2 proteins

ProteinN (3)

ProteinS (2)

NSP13 (1)

ORF3a (1)

ORF6 (1)


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SARS-CoV-2 Proteins
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    Massively parallel interrogation of protein fragment secretability using SECRiFY reveals features influencing secretory system transit

    Authors: Siqi Wu; Chang Tian; Panpan Liu; Dongjie Guo; Wei Zheng; Xiaoqiang Huang; Yang Zhang; Lijun Liu; Abhilash Dhal; Shelli F Farhadian; Lynn Fitzgibbons; John Fournier; Michael Jhatro; Gregory Jordan; Debra Kessler; Jon Klein; Carolina Lucas; Larry L Luchsinger; Brian Martinez; Mary C Muenker; Lauren Pischel; Jack Reifert; Jaymie R Sawyer; Rebecca Waitz; Elsio A Wunder Jr.; Minlu Zhang; - Yale IMPACT Team; Akiko Iwasaki; Albert I Ko; John C Shon

    doi:10.1101/241349 Date: 2020-11-26 Source: bioRxiv

    While transcriptome- and proteome-wide technologies to assess processes in protein biogenesis are now widely available, we still lack global approaches to assay post-ribosomal biogenesis events, in particular those occurring in the eukaryotic secretory system. We here developed a method, SECRiFY, to simultaneously assess the secretability of >105 protein fragments by two yeast species, S. cerevisiae and P. pastoris, using custom fragment libraries, surface display and a sequencing-based readout. Screening human proteome fragments with a median size of 50 - 100 amino acids, we generated datasets that enable datamining into protein features underlying secretability, revealing a striking role for intrinsic disorder MESHD and chain flexibility. SECRiFY is the first methodology that generates sufficient amounts of annotated data for advanced machine learning methods to deduce secretability predictors. The finding that secretability is indeed a learnable feature of protein sequences is of significant impact in the broad area of recombinant protein expression and de novo protein design.

    Understanding Structural Malleability of the SARS-CoV-2 Proteins and their Relation to the Comorbidities

    Authors: Sagnik Sen; Ashmita Dey; Sanghamitra Bandyopadhyay; Ujjwal Maulik; Vladimir Uversky

    doi:10.21203/rs.3.rs-82352/v1 Date: 2020-09-23 Source: ResearchSquare

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a causative agent of the coronavirus disease MESHD ( CoVID-19 MESHD), is a part of the β-coronaviridae family. In comparison with two other members of this family of coronaviruses infecting humans ( SARS-CoV and Middle East Respiratory Syndrome MESHD ( MERS MESHD) CoV), SARS-CoV-2 showed the most severe effects on the entire Earth population causing world-wide CoVID-19 pandemic MESHD. SARS-CoV-2 contains five major protein classes, such as four structural proteins (Nucleocapsid (N PROTEIN), Membrane (M), Envelop (E), and Spike Glycoprotein PROTEIN (S)) and Replicase polyproteins (R), which are synthesized as two polyproteins ( ORF1a PROTEIN and ORF1ab PROTEIN) that are subsequently processed into 12 nonstructural proteins by three viral proteases. All these proteins share high sequence similarity with their SARS-CoV counterparts. Due to the severity of the current situation, most of the SARS-CoV-2-related research is focused on finding therapeutic solutions and the analysis of comorbidities during infection. However, studies on the peculiarities of the amino acid sequences of viral protein classes and their structure space analysis throughout the evolutionary time-frame are limited. At the same time, due to their structural malleability, viral proteins can be directly or indirectly associated with the dysfunctionality of the host cell proteins, which may lead to comorbidities during the infection and at the post infection stage. To fill these gaps, we conducted the evolutionary sequence-structure analysis of the viral protein classes to evaluate the rate of their evolutionary malleability. We also looked at the intrinsic disorder propensities of these viral proteins and confirmed that although they typically do not have long intrinsically disordered regions (IDRs), all of them have at least some levels of intrinsic disorder MESHD. Furthermore, short IDRs found in viral proteins are extremely effective and prioritize the proteins for host cell interactions, which may lead to host cell dysfunction. Next, the associations of viral proteins with the host cell proteins were studied, and a list of diseases which are associated with such host cell proteins was developed. Other than the usual set of diseases, we have identified some maladies, which may happen after the recovery from the infections. Comparison of the expression rates of the host cell proteins during the diseases suggested the existence of two distinct classes. First class includes proteins, which are directly associated with certain sets of diseases, where they have shared similar activities. Second class is related to the cytokine storm-mediated pro- inflammation MESHD (already known for its role in acute respiratory distress syndrome MESHD, ARDS MESHD), and neuroinflammation may trigger some of the neurological malignancies and neurodegenerative and neuropsychiatric diseases MESHD. Finally, since the transmembrane serine protease 2 ( TMPRSS2 HGNC), which is one of the leading proteins associated with the viral uptake, is an androgen-mediated protein, our study suggested that males and postmenopausal females can be more susceptible to the SARS-CoV-2 infection MESHD.

    New Pathways of Mutational Change in SARS-CoV-2 Proteomes Involve Regions of Intrinsic Disorder Important for Virus Replication and Release

    Authors: Tre Tomaszewski; Ryan S DeVries; Mengyi Dong; Gitanshu Bhatia; Miles D Norsworthy; Xuying Zheng; Gustavo Caetano-Anolles

    doi:10.1101/2020.07.31.231472 Date: 2020-07-31 Source: bioRxiv

    The massive worldwide spread of the SARS-CoV-2 virus is fueling the COVID-19 MESHD COVID-19 MESHD pandemic. Since the first whole-genome sequence was published in January 2020, a growing database of tens of thousands of viral genomes has been constructed. This offers opportunities to study pathways of molecular change in the expanding viral population that can help identify molecular culprits of virulence and virus spread. Here we investigate the genomic accumulation of mutations at various time points of the early pandemic to identify changes in mutationally highly active genomic regions that are occurring worldwide. We used the Wuhan NC_045512.2 sequence as a reference and sampled 15,342 indexed sequences from GISAID, translating them into proteins and grouping them by month of deposition. The per-position amino acid frequencies and Shannon entropies of the coding sequences were calculated for each month, and a map of intrinsic disorder MESHD regions and binding sites was generated. The analysis revealed dominant variants, most of which were located in loop regions and on the surface of the proteins. Mutation entropy decreased between March and April of 2020 after steady increases at several sites, including the D614G mutation site of the spike (S) protein PROTEIN that was previously found associated with higher case fatality rates and at sites of the NSP 12 polymerase and the NSP13 PROTEIN helicase proteins. Notable expanding mutations include R203K and G204R of the nucleocapsid (N) protein PROTEIN inter-domain linker region and G251V of the viroporin encoded by ORF3a PROTEIN between March and April. The regions spanning these mutations exhibited significant intrinsic disorder MESHD, which was enhanced and decreased by the N-protein PROTEIN and viroporin 3a protein mutations, respectively. These results predict an ongoing mutational shift from the spike and replication complex to other regions, especially to encoded molecules known to represent major {beta}-interferon antagonists. The study provides valuable information for therapeutics and vaccine design, as well as insight into mutation tendencies that could facilitate preventive control.

    Shell Disorder Analysis Suggests That Pangolins Offered a Window for a Silent Spread of an Attenuated SARS-CoV-2 Precursor among Humans

    Authors: Gerard Kian-Meng Goh; A. Keith Dunker; James A. Foster; Vladimir N. Uversky

    id:202006.0327/v1 Date: 2020-06-28 Source: Preprints.org

    A model to predict the relative levels of respiratory and fecal-oral transmission potentials of coronaviruses (CoVs) by measuring the percentage of protein intrinsic disorder MESHD ( PID MESHD) of the M (Membrane) and N (nucleoprotein PROTEIN) proteins in their outer and inner shells, respectively, was built before the MERS-CoV outbreak. Application of this model to the 2003 SARS-CoV indicated that this virus with MPID = 8.6% and NPID = 50.2% falls into group B, which consists of CoVs with intermediate levels of both fecal-oral and respiratory transmission potentials. Further validation of the model came with MERS-CoV MESHD (MPID = 9%, NPID = 44%) and SARS-CoV-2 (MPID = 5.5%, NPID = 48%) falling into the groups C and B, respectively. Group C contains CoVs with higher fecal-oral but lower respiratory transmission potentials. Unlike SARS-CoV, SARS-CoV-2 MESHD with MPID = 5.5% has one of the hardest outer shells among CoVs. This shell hardness MESHD is believed to be responsible for high viral loads in the mucus and saliva making it more contagious than SARS-CoV MESHD. The hard shell is able to resist the anti-microbial enzymes in body fluids. Further searches have found that high rigidity MESHD of outer shell is characteristic for the CoVs of burrowing animals, such as rabbits (MPID = 5.6%) and pangolins (MPID = 5-6%), which are in contact with the buried feces. A closer inspection of pangolin-CoVs from 2017-19 reveals that these animals provided a unique window of opportunity for the entry of an attenuated SARS-CoV-2 precursor into the human population in 2017 or earlier, with the subsequent slow and silent spread as a mild cold that followed by its mutations into the current more virulent form. Evidence of this lies in the similarity of shell disorder MESHD and genetic proximity of the pangolin-CoVs to SARS-CoV-2 (~90%). A 2017 pangolin-CoV strain shows evidence of higher levels of attenuation and higher fecal-oral transmission associated with lower human infectivity via having lower NPID (44.8%). Our shell disorder analysis also revealed that lower inner shell disorder MESHD is associated with the lesser virulence in a variety of viruses.

    Dark proteome of Newly Emerged SARS-CoV-2 in Comparison with Human and Bat Coronaviruses

    Authors: Rajanish Giri; Taniya Bhardwaj; Meenakshi Shegane; Bhuvaneshwari R Gehi; Prateek Kumar; Kundlik Gadhave; Christopher J. Oldfield; Vladimir N Uversky

    doi:10.1101/2020.03.13.990598 Date: 2020-03-14 Source: bioRxiv

    Recently emerged coronavirus designated as SARS-CoV-2 (also known as 2019 novel coronavirus (2019-nCoV) or Wuhan coronavirus) is a causative agent of coronavirus disease 2019 MESHD ( COVID-19 MESHD), which is rapidly spreading throughout the world now. More than 9,00,000 cases of SARS-CoV-2 infection MESHD and more than 47,000 COVID-19 MESHD-associated mortalities have been reported worldwide till the writing of this article, and these numbers are increasing every passing hour. World Health Organization (WHO) has declared the SARS-CoV-2 spread as a global public health emergency and admitted that the COVID-19 MESHD is a pandemic now. The multiple sequence alignment data correlated with the already published reports on the SARS-CoV-2 evolution and indicated that this virus is closely related to the bat Severe Acute Respiratory Syndrome-like coronavirus MESHD (bat SARS-like CoV) and the well-studied Human SARS coronavirus ( SARS CoV MESHD). The disordered regions in viral proteins are associated with the viral infectivity and pathogenicity. Therefore, in this study, we have exploited a set of complementary computational approaches to examine the dark proteomes of SARS-CoV-2, bat SARS-like, and human SARS CoVs by analysing the prevalence of intrinsic disorder MESHD in their proteins. According to our findings, SARS-CoV-2 proteome contains very significant levels of structural order. In fact, except for Nucleocapsid, Nsp8, and ORF6 PROTEIN, the vast majority of SARS-CoV-2 proteins MESHD are mostly ordered proteins containing less intrinsically disordered protein regions (IDPRs). However, IDPRs found in SARS-CoV-2 proteins are functionally important. For example, cleavage sites in its replicase 1ab polyprotein are found to be highly disordered, and almost all SARS-CoV-2 proteins were shown to contain molecular recognition features (MoRFs), which are intrinsic disorder-based protein-protein interaction sites that are commonly utilized by proteins for interaction with specific partners. The results of our extensive investigation of the dark side of the SARS-CoV-2 proteome will have important implications for the structural and non-structural biology of SARS or SARS-like coronaviruses. SignificanceThe infection caused by a novel coronavirus (SARS-CoV-2) that causes severe respiratory disease with pneumonia-like symptoms in humans is responsible for the current COVID-19 pandemic MESHD. No in-depth information on structures and functions of SARS-CoV-2 proteins is currently available in the public domain, and no effective anti-viral drugs and/or vaccines are designed for the treatment of this infection. Our study provides the first comparative analysis of the order- and disorder-based features of the SARS-CoV-2 proteome relative to human SARS and bat CoV that may be useful for structure-based drug discovery.

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MeSH Disease
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