scholarly journals Use of viral motif mimicry improves the proteome-wide discovery of human linear motifs

2021 ◽  
Author(s):  
Bishoy Wadie ◽  
Vitalii Kleshchevnikov ◽  
Elissavet Sandaltzopoulou ◽  
Caroline Benz ◽  
Evangelia Petsalaki
Keyword(s):  
Molecular Mimicry ◽  
Cell Signalling ◽  
Interaction Network ◽  
Viral Proteins ◽  
Search Space ◽  
Human Protein ◽  
Linear Motif ◽  
Cell Functions ◽  
Motif Prediction ◽  
Linear Motifs

Linear motifs have an integral role in dynamic cell functions including cell signalling, the cell cycle and others. However, due to their small size, low complexity, degenerate nature, and frequent mutations, identifying novel functional motifs is a challenging task. Viral proteins rely extensively on the molecular mimicry of cellular linear motifs for modifying cell signalling and other processes in ways that favour viral infection. This study aims to discover human linear motifs convergently evolved also in disordered regions of viral proteins, under the hypothesis that these will result in enrichment in functional motif instances. We systematically apply computational motif prediction, combined with implementation of several functional and structural filters to the most recent publicly available human-viral and human-human protein interaction network. By limiting the search space to the sequences of viral proteins, we observed an increase in the sensitivity of motif prediction, as well as improved enrichment in known instances compared to the same analysis using only human protein interactions. We identified > 8,400 motif instances at various confidence levels, 105 of which were supported by all functional and structural filters applied. Overall, we provide a pipeline to improve the identification of functional linear motifs from interactomics datasets and a comprehensive catalogue of putative human motifs that can contribute to our understanding of the human domain-linear motif code and the mechanisms of viral interference with this.

scholarly journals Short linear motif acquisition, exon formation and alternative splicing determine a pathway to diversity for NCoR-family co-repressors

Open Biology ◽  
2015 ◽  
Vol 5 (8) ◽  
pp. 150063 ◽  
Author(s):  
Stephen Short ◽  
Tessa Peterkin ◽  
Matthew Guille ◽  
Roger Patient ◽  
Colin Sharpe
Keyword(s):  
Alternative Splicing ◽  
Gene Sequence ◽  
Species Differences ◽  
Single Point ◽  
Stem Cell Differentiation ◽  
Single Point Mutation ◽  
Linear Motif ◽  
Cellular Context ◽  
Alternatively Spliced ◽  
Linear Motifs

Vertebrate NCoR-family co-repressors play central roles in the timing of embryo and stem cell differentiation by repressing the activity of a range of transcription factors. They interact with nuclear receptors using short linear motifs (SLiMs) termed co-repressor for nuclear receptor (CoRNR) boxes. Here, we identify the pathway leading to increasing co-repressor diversity across the deuterostomes. The final complement of CoRNR boxes arose in an ancestral cephalochordate, and was encoded in one large exon; the urochordates and vertebrates then split this region between 10 and 12 exons. In Xenopus , alternative splicing is prevalent in NCoR2, but absent in NCoR1. We show for one NCoR1 exon that alternative splicing can be recovered by a single point mutation, suggesting NCoR1 lost the capacity for alternative splicing. Analyses in Xenopus and zebrafish identify that cellular context, rather than gene sequence, predominantly determines species differences in alternative splicing. We identify a pathway to diversity for the NCoR family beginning with the addition of a SLiM, followed by gene duplication, the generation of alternatively spliced isoforms and their differential deployment.

scholarly journals Resources to Discover and Use Short Linear Motifs in Viral Proteins

2020 ◽  
Vol 38 (1) ◽  
pp. 113-127 ◽  
Author(s):  
Peter Hraber ◽  
Paul E. O’Maille ◽  
Andrew Silberfarb ◽  
Katie Davis-Anderson ◽  
Nicholas Generous ◽  
...  
Keyword(s):  
Viral Proteins ◽  
Short Linear Motifs ◽  
Linear Motifs

scholarly journals Identification of COVID-19 Infection-Related Human Genes Based on a Random Walk Model in a Virus–Human Protein Interaction Network

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
YuHang Zhang ◽  
Tao Zeng ◽  
Lei Chen ◽  
ShiJian Ding ◽  
Tao Huang ◽  
...  
Keyword(s):  
Random Walk ◽  
Infectious Diseases ◽  
Protein Interaction ◽  
Protein Interaction Network ◽  
Disease Outbreaks ◽  
Interaction Network ◽  
Random Walk Model ◽  
Human Protein ◽  
Human Beings ◽  
Human Protein Interaction

Coronaviruses are specific crown-shaped viruses that were first identified in the 1960s, and three typical examples of the most recent coronavirus disease outbreaks include severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19. Particularly, COVID-19 is currently causing a worldwide pandemic, threatening the health of human beings globally. The identification of viral pathogenic mechanisms is important for further developing effective drugs and targeted clinical treatment methods. The delayed revelation of viral infectious mechanisms is currently one of the technical obstacles in the prevention and treatment of infectious diseases. In this study, we proposed a random walk model to identify the potential pathological mechanisms of COVID-19 on a virus–human protein interaction network, and we effectively identified a group of proteins that have already been determined to be potentially important for COVID-19 infection and for similar SARS infections, which help further developing drugs and targeted therapeutic methods against COVID-19. Moreover, we constructed a standard computational workflow for predicting the pathological biomarkers and related pharmacological targets of infectious diseases.

scholarly journals Identification ofInfluenza A/H7N9 Virus Infection-Related Human Genes Based on Shortest Paths in a Virus-Human Protein Interaction Network

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Ning Zhang ◽  
Min Jiang ◽  
Tao Huang ◽  
Yu-Dong Cai
Keyword(s):  
Virus Infection ◽  
Protein Interaction ◽  
Protein Interaction Network ◽  
Influenza A ◽  
Shortest Paths ◽  
Interaction Network ◽  
Human Protein ◽  
H7n9 Virus ◽  
Human Protein Interaction ◽  
Human Genes

The recently emergingInfluenza A/H7N9 virus is reported to be able to infect humans and cause mortality. However, viral and host factors associated with the infection are poorly understood. It is suggested by the “guilt by association” rule that interacting proteins share the same or similar functions and hence may be involved in the same pathway. In this study, we developed a computational method to identifyInfluenza A/H7N9 virus infection-related human genes based on this rule from the shortest paths in a virus-human protein interaction network. Finally, we screened out the most significant 20 human genes, which could be the potential infection related genes, providing guidelines for further experimental validation. Analysis of the 20 genes showed that they were enriched in protein binding, saccharide or polysaccharide metabolism related pathways and oxidative phosphorylation pathways. We also compared the results with those from human rhinovirus (HRV) and respiratory syncytial virus (RSV) by the same method. It was indicated that saccharide or polysaccharide metabolism related pathways might be especially associated with the H7N9 infection. These results could shed some light on the understanding of the virus infection mechanism, providing basis for future experimental biology studies and for the development of effective strategies for H7N9 clinical therapies.

scholarly journals Identification and characterization of differentially active pools of type IIα phosphatidylinositol 4-kinase activity in unstimulated A431 cells

2003 ◽  
Vol 376 (2) ◽  
pp. 497-503 ◽  
Author(s):  
Mark G. WAUGH ◽  
Shane MINOGUE ◽  
Deena BLUMENKRANTZ ◽  
J. Simon ANDERSON ◽  
J. Justin HSUAN
Keyword(s):  
Kinase Activity ◽  
Cell Signalling ◽  
Cell Types ◽  
Intrinsic Activity ◽  
A431 Cells ◽  
Cell Functions ◽  
Subcellular Membrane ◽  
Phosphatidylinositol Kinase ◽  
Wide Range ◽  
Phosphatidylinositol 4

The seven known polyphosphoinositides have been implicated in a wide range of regulated and constitutive cell functions, including cell-surface signalling, vesicle trafficking and cytoskeletal reorganization. In order to understand the spatial and temporal control of these diverse cell functions it is necessary to characterize the subcellular distribution of a wide variety of polyphosphoinositide synthesis and signalling events. The predominant phosphatidylinositol kinase activity in many mammalian cell types involves the synthesis of the signalling precursor, phosphatidylinositol 4-phosphate, in a reaction catalysed by the recently cloned PI4KIIα (type IIα phosphatidylinositol 4-kinase). However the regulation of this enzyme and the cellular distribution of its product in different organelles are very poorly understood. This report identifies the existence, in unstimulated cells, of two major subcellular membrane fractions, which contain PI4KIIα possessing different levels of intrinsic activity. Separation of these membranes from each other and from contaminating activities was achieved by density gradient ultracentrifugation at pH 11 in a specific detergent mixture in which both membrane fractions, but not other membranes, were insoluble. Kinetic comparison of the purified membrane fractions revealed a 4-fold difference in Km for phosphatidylinositol and a 3.5-fold difference in Vmax, thereby indicating a different mechanism of regulation to that described previously for agonist-stimulated cells. These marked differences in basal activity and the occurrence of this isozyme in multiple organelles emphasize the need to investigate cell signalling via PI4KIIα at the level of individual organelles rather than whole-cell lysates.

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