Comparing protein structures with RINspector automation in Cytoscape

Brysbaert, Guillaume; Mauri, Théo; Lensink, Marc F.

doi:10.12688/f1000research.14298.2

Cited by 14 publications

(10 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interactions between human proteins and SARS-CoV-2 viral proteins were obtained from Human Protein Atlas (HPA). Protein interaction network is created using Cytoscape version 3.6.1 [ 13 ]. Edge-weighted spring-embedded layout was used for the network.…”

Section: Methodsmentioning

confidence: 99%

Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells

Appelberg

Gupta

Akusjärvi

et al. 2020

Emerging Microbes & Infections

232

261

View full text Add to dashboard Cite

How severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections engage cellular host pathways and innate immunity in infected cells remains largely elusive. We performed an integrative proteo-transcriptomics analysis in SARS-CoV-2 infected Huh7 cells to map the cellular response to the invading virus over time. We identified four pathways, ErbB, HIF-1, mTOR and TNF signaling, among others that were markedly modulated during the course of the SARS-CoV-2 infection in vitro. Western blot validation of the downstream effector molecules of these pathways revealed a dose-dependent activation of Akt, mTOR, S6K1 and 4E-BP1 at 24 hours post infection (hpi). However, we found a significant inhibition of HIF-1α through 24hpi and 48hpi of the infection, suggesting a crosstalk between the SARS-CoV-2 and the Akt/mTOR/HIF-1 signaling pathways. Inhibition of the mTOR signaling pathway using Akt inhibitor MK-2206 showed a significant reduction in virus production. Further investigations are required to better understand the molecular sequelae in order to guide potential therapy in the management of severe coronavirus disease 2019 (COVID-19) patients.

show abstract

Section: Methodsmentioning

confidence: 99%

Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells

Appelberg

Gupta

Akusjärvi

et al. 2020

Emerging Microbes & Infections

232

261

View full text Add to dashboard Cite

show abstract

“…The betweenness centrality metric is also computed by evaluating the average shortest path length (ASPL) change by systematically removing individual nodes. 108 , 109 A Z -score is then computed for each node based on the change of ASPL compared to the initial one.…”

Section: Materials and Methodsmentioning

confidence: 99%

Dynamic Network Modeling of Allosteric Interactions and Communication Pathways in the SARS-CoV-2 Spike Trimer Mutants: Differential Modulation of Conformational Landscapes and Signal Transmission via Cascades of Regulatory Switches

2021

View full text Add to dashboard Cite

The rapidly growing body of structural and biochemical studies of the SARS-CoV-2 spike glycoprotein has revealed a variety of distinct functional states with radically different arrangements of the receptor-binding domain, highlighting a remarkable function-driven conformational plasticity and adaptability of the spike proteins. In this study, we examined molecular mechanisms underlying conformational and dynamic changes in the SARS-CoV-2 spike mutant trimers through the lens of dynamic analysis of allosteric interaction networks and atomistic modeling of signal transmission. Using an integrated approach that combined coarsegrained molecular simulations, protein stability analysis, and perturbation-based modeling of residue interaction networks, we examined how mutations in the regulatory regions of the SARS-CoV-2 spike protein can differentially affect dynamics and allosteric signaling in distinct functional states. The results of this study revealed key functional regions and regulatory centers that govern collective dynamics, allosteric interactions, and control signal transmission in the SARS-CoV-2 spike proteins. We found that the experimentally confirmed regulatory hotspots that dictate dynamic switching between conformational states of the SARS-CoV-2 spike protein correspond to the key hinge sites and global mediating centers of the allosteric interaction networks. The results of this study provide a novel insight into allosteric regulatory mechanisms of SARS-CoV-2 spike proteins showing that mutations at the key regulatory positions can differentially modulate distribution of states and determine topography of signal communication pathways operating through state-specific cascades of control switch points. This analysis provides a plausible strategy for allosteric probing of the conformational equilibrium and therapeutic intervention by targeting specific hotspots of allosteric interactions and communications in the SARS-CoV-2 spike proteins.

show abstract

“…Residue Interaction Networks (RINs) were generated for every best model of all the docking runs performed between the ETS domain of Ets-1 and each homologous BRCT or SAP structure (one representative structure of each group). They were created with an in-house C program considering a residue-residue contact when the distance between any atom pair of both residues was found between 2.5 Å and 5 Å. Residue Centrality Analyses (RCA) were performed with the RINspector app [25,26] for Cytoscape. We considered as central a residue with a Z -score ≥ 2.…”

Section: Methodsmentioning

confidence: 99%

Identification of Novel Interaction Partners of Ets-1: Focus on DNA Repair

Brysbaert

Ruyck

Aumercier

et al. 2019

Genes

Self Cite

View full text Add to dashboard Cite

The transcription factor Ets-1 (ETS proto-oncogene 1) shows low expression levels except in specific biological processes like haematopoiesis or angiogenesis. Elevated levels of expression are observed in tumor progression, resulting in Ets-1 being named an oncoprotein. It has recently been shown that Ets-1 interacts with two DNA repair enzymes, PARP-1 (poly(ADP-ribose) polymerase 1) and DNA-PK (DNA-dependent protein kinase), through two different domains and that these interactions play a role in cancer. Considering that Ets-1 can bind to distinctly different domains of two DNA repair enzymes, we hypothesized that the interaction can be transposed onto homologs of the respective domains. We have searched for sequence and structure homologs of the interacting ETS(Ets-1), BRCT(PARP-1) and SAP(DNA-PK) domains, and have identified several candidate binding pairs that are currently not annotated as such. Many of the Ets-1 partners are associated to DNA repair mechanisms. We have applied protein-protein docking to establish putative interaction poses and investigated these using centrality analyses at the protein residue level. Most of the identified poses are virtually similar to our recently established interaction model for Ets-1/PARP-1 and Ets-1/DNA-PK. Our work illustrates the potentially high number of interactors of Ets-1, in particular involved in DNA repair mechanisms, which shows the oncoprotein as a potential important regulator of the mechanism.

show abstract

Comparing protein structures with RINspector automation in Cytoscape

Cited by 14 publications

References 14 publications

Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells

Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells

Dynamic Network Modeling of Allosteric Interactions and Communication Pathways in the SARS-CoV-2 Spike Trimer Mutants: Differential Modulation of Conformational Landscapes and Signal Transmission via Cascades of Regulatory Switches

Identification of Novel Interaction Partners of Ets-1: Focus on DNA Repair

Contact Info

Product

Resources

About