protein interactome
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Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 140
Author(s):  
Georgios N. Dimitrakopoulos ◽  
Maria I. Klapa ◽  
Nicholas K. Moschonas

After more than fifteen years from the first high-throughput experiments for human protein–protein interaction (PPI) detection, we are still wondering how close the completion of the genome-scale human PPI network reconstruction is, what needs to be further explored and whether the biological insights gained from the holistic investigation of the current network are valid and useful. The unique structure of PICKLE, a meta-database of the human experimentally determined direct PPI network developed by our group, presently covering ~80% of the UniProtKB/Swiss-Prot reviewed human complete proteome, enables the evaluation of the interactome expansion by comparing the successive PICKLE releases since 2013. We observe a gradual overall increase of 39%, 182%, and 67% in protein nodes, PPIs, and supporting references, respectively. Our results indicate that, in recent years, (a) the PPI addition rate has decreased, (b) the new PPIs are largely determined by high-throughput experiments and mainly concern existing protein nodes and (c), as we had predicted earlier, most of the newly added protein nodes have a low degree. These observations, combined with a largely overlapping k-core between PICKLE releases and a network density increase, imply that an almost complete picture of a structurally defined network has been reached. The comparative unsupervised application of two clustering algorithms indicated that exploring the full interactome topology can reveal the protein neighborhoods involved in closely related biological processes as transcriptional regulation, cell signaling and multiprotein complexes such as the connexon complex associated with cancers. A well-reconstructed human protein interactome is a powerful tool in network biology and medicine research forming the basis for multi-omic and dynamic analyses.


Author(s):  
Dhana G. Gorasia ◽  
Ignacio Lunar Silva ◽  
Catherine A. Butler ◽  
Maïalène Chabalier ◽  
Thierry Doan ◽  
...  

The T9SS is a newly identified protein secretion system of the Fibrobacteres - Chlorobi - Bacteroidetes superphylum used by pathogens associated with diseases of humans, fish, and poultry for the secretion and cell surface attachment of virulence factors. The T9SS comprises three known modules: (i) the trans-envelope core module comprising the PorL/M motor and the PorK/N ring, (ii) the outer membrane Sov translocon, and (iii) the cell surface attachment complex.


2022 ◽  
Vol 14 (1) ◽  
Author(s):  
Jiansong Fang ◽  
Pengyue Zhang ◽  
Quan Wang ◽  
Chien-Wei Chiang ◽  
Yadi Zhou ◽  
...  

Abstract Background Genome-wide association studies (GWAS) have identified numerous susceptibility loci for Alzheimer’s disease (AD). However, utilizing GWAS and multi-omics data to identify high-confidence AD risk genes (ARGs) and druggable targets that can guide development of new therapeutics for patients suffering from AD has heretofore not been successful. Methods To address this critical problem in the field, we have developed a network-based artificial intelligence framework that is capable of integrating multi-omics data along with human protein–protein interactome networks to accurately infer accurate drug targets impacted by GWAS-identified variants to identify new therapeutics. When applied to AD, this approach integrates GWAS findings, multi-omics data from brain samples of AD patients and AD transgenic animal models, drug-target networks, and the human protein–protein interactome, along with large-scale patient database validation and in vitro mechanistic observations in human microglia cells. Results Through this approach, we identified 103 ARGs validated by various levels of pathobiological evidence in AD. Via network-based prediction and population-based validation, we then showed that three drugs (pioglitazone, febuxostat, and atenolol) are significantly associated with decreased risk of AD compared with matched control populations. Pioglitazone usage is significantly associated with decreased risk of AD (hazard ratio (HR) = 0.916, 95% confidence interval [CI] 0.861–0.974, P = 0.005) in a retrospective case-control validation. Pioglitazone is a peroxisome proliferator-activated receptor (PPAR) agonist used to treat type 2 diabetes, and propensity score matching cohort studies confirmed its association with reduced risk of AD in comparison to glipizide (HR = 0.921, 95% CI 0.862–0.984, P = 0.0159), an insulin secretagogue that is also used to treat type 2 diabetes. In vitro experiments showed that pioglitazone downregulated glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase (CDK5) in human microglia cells, supporting a possible mechanism-of-action for its beneficial effect in AD. Conclusions In summary, we present an integrated, network-based artificial intelligence methodology to rapidly translate GWAS findings and multi-omics data to genotype-informed therapeutic discovery in AD.


2022 ◽  
Author(s):  
Marius Walter ◽  
Irene P Chen ◽  
Albert Vallejo-Gracia ◽  
Ik-Jung Kim ◽  
Olga Bielska ◽  
...  

SARS-CoV-2 non-structural protein Nsp14 is a highly conserved enzyme necessary for viral replication. Nsp14 forms a stable complex with non-structural protein Nsp10 and exhibits exoribonuclease and N7-methyltransferase activities. Protein-interactome studies identified human sirtuin 5 (SIRT5) as a putative binding partner of Nsp14. SIRT5 is an NAD-dependent protein deacylase critical for cellular metabolism that removes succinyl and malonyl groups from lysine residues. Here we investigated the nature of this interaction and the role of SIRT5 during SARS-CoV-2 infection. We showed that SIRT5 stably interacts with Nsp14, but not with Nsp10, suggesting that SIRT5 and Nsp10 are parts of separate complexes. We found that SIRT5 catalytic domain is necessary for the interaction with Nsp14, but that Nsp14 does not appear to be directly deacylated by SIRT5. Furthermore, knock-out of SIRT5 or treatment with specific SIRT5 inhibitors reduced SARS-CoV-2 viral levels in cell-culture experiments. SIRT5 knock-out cells expressed higher basal levels of innate immunity markers and mounted a stronger antiviral response. Our results indicate that SIRT5 is a proviral factor necessary for efficient viral replication, which opens novel avenues for therapeutic interventions.


eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Jenna R Christensen ◽  
Agnieszka A Kendrick ◽  
Joey B Truong ◽  
Adriana Aguilar-Maldonado ◽  
Vinit Adani ◽  
...  

In eukaryotic cells, intracellular components are organized by the microtubule motors cytoplasmic dynein-1 (dynein) and kinesins, which are linked to cargos via adaptor proteins. While ~40 kinesins transport cargo toward the plus end of microtubules, a single dynein moves cargo in the opposite direction. How dynein transports a wide variety of cargos remains an open question. The FTS-Hook-FHIP ('FHF') cargo adaptor complex links dynein to cargo in mammals and fungi. As human cells have three Hooks and four FHIP proteins, we hypothesized that the combinatorial assembly of different Hook and FHIP proteins could underlie dynein cargo diversity. Using proteomic approaches, we determine the protein 'interactome' of each FHIP protein. Live-cell imaging and biochemical approaches show that different FHF complexes associate with distinct motile cargos. These complexes also move with dynein and its cofactor dynactin in single-molecule in vitro reconstitution assays. Complexes composed of FTS, FHIP1B, and Hook1/Hook3 co-localize with Rab5-tagged early endosomes via a direct interaction between FHIP1B and GTP-bound Rab5. In contrast, complexes composed of FTS, FHIP2A and Hook2 colocalize with Rab1A-tagged ER-to-Golgi cargos and FHIP2A is involved in the motility of Rab1A tubules. Our findings suggest that combinatorial assembly of different FTS-Hook-FHIP complexes is one mechanism dynein uses to achieve cargo specificity.


2021 ◽  
Author(s):  
Paola Lecca ◽  
Bruno Carpentieri ◽  
Paolo Sylos Labini ◽  
Flavio Vella ◽  
Emidio Troiani ◽  
...  
Keyword(s):  

2021 ◽  
Author(s):  
Justin Michael Watkins ◽  
Alan M. Jones ◽  
Justin Walley ◽  
Natalie M Clark ◽  
Daisuke Urano ◽  
...  

flg22 is a 22 amino peptide released from bacterial flagellin a Microbe Associated Molecular 51 Pattern ( that is recognized by the plant cell as a signal indicating that bacteria are present. On its own, flg22 initiates a rapid increase in cytoplasmic calcium, extracellular reactive oxygen species, and activation of a Mitogen Activated Protein Kinase (cascade all of which are activated within 15 minutes after the cell perceives flg22. Here we show a massive change in protein abundance and phosphorylation state of the Arabidopsis root cell proteome within this 15 minute duration in wildtype and a mutant deficient in G protein coupled signaling Integration of phosphoproteome with protein protein interactome data followed by network topology analyses discovered that many of the flg22 induced phosphoproteome changes fall on proteins that comprise the G protein interactome and on the most highly populated hubs of the immunity network approximately 95% of the phosphorylation changes in the G protein interactome depend on a functional heterotrimeric G protein complex some occur on proteins that interact directly with components of G coupled signal transduction. One of these is ATBα, a substrate recognition sub-unit of the PP2A Ser/Thr phosphatase and an interactor to Arabidopsis thaliana REGULATOR OF G SIGNALING 1 protein (a 7 transmembrane spanning modulator of the nucleotide binding state of the core G protein complex. AtRGS1 is phosphorylated by BAK1, a component of the flg22 receptor, to initiate AtRGS1 endocytosis. A null mutation of ATB α confer s high 67 basal endocytosis of AtRGS1 suggesting sustained phosphorylated status. Loss of ATB α confers 68 trait s associated with loss of AtRGS1. Because the basal level of AtRGS1 is lower in the atbα null mutant in a proteasome dependent manner we propose that phosphorylation dependent endocytosis of AtRGS1 is part of a mechanism to degrade AtRGS1 which then sustains activation of the 71 G protein complex Thus, the role of ATB α is now established as a central component of phosphorylation dependent regulation of system dynamics in innate immunity


2021 ◽  
Author(s):  
Justin M Watkins ◽  
Natalie M Clark ◽  
Gaoyuan Song ◽  
Celio Cabral Oliveira ◽  
Bharat Mishra ◽  
...  

flg22 is recognized by the plant cell as a signal indicating that bacteria are present. Here we show a rapid and massive change in protein abundance and phosphorylation state of the Arabidopsis root cell proteome in wildtype and a mutant deficient in G-protein coupled signaling. Many of the flg22-induced changes fall on proteins comprising the G protein interactome and on highly populated hubs of the immunity network. Approximately 95% of the phosphorylation changes in the G-protein interactome depend on a functional G protein complex; some on proteins in the G protein interactome. One of these is ATB?, an interactor to REGULATOR OF G SIGNALING 1 protein (AtRGS1), a 7-transmembrane spanning modulator of the nucleotide-binding state of the core G protein complex. A null mutation of ATB? confers basal endocytosis of AtRGS1. AtRGS1 level is lower in the atb? mutant in a proteasome-dependent manner. We propose that phosphorylation-dependent endocytosis of AtRGS1 is part of the mechanism to degrade AtRGS1 thus sustaining activation of the G protein complex required for regulation of system dynamics in innate immunity.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ovidio Jiménez Martín ◽  
Andreas Schlosser ◽  
Rhoikos Furtwängler ◽  
Jenny Wegert ◽  
Manfred Gessler

Abstract Background Wilms tumor (WT) is the most common renal tumor in childhood. Among others, MYCN copy number gain and MYCN P44L and MAX R60Q mutations have been identified in WT. MYCN encodes a transcription factor that requires dimerization with MAX to activate transcription of numerous target genes. MYCN gain has been associated with adverse prognosis in different childhood tumors including WT. The MYCN P44L and MAX R60Q mutations, located in either the transactivating or basic helix-loop-helix domain, respectively, are predicted to be damaging by different pathogenicity prediction tools, but the functional consequences remain to be characterized. Methods We screened a large cohort of unselected WTs for MYCN and MAX alterations. Wild-type and mutant protein function were characterized biochemically, and we analyzed the N-MYC protein interactome by mass spectrometric analysis of N-MYC containing protein complexes. Results Mutation screening revealed mutation frequencies of 3% for MYCN P44L and 0.9% for MAX R60Q that are associated with a higher risk of relapse. Biochemical characterization identified a reduced transcriptional activation potential for MAX R60Q, while the MYCN P44L mutation did not change activation potential or protein stability. The protein interactome of N-MYC-P44L was likewise not altered as shown by mass spectrometric analyses of purified N-MYC complexes. Nevertheless, we could identify a number of novel N-MYC partner proteins, e.g. PEG10, YEATS2, FOXK1, CBLL1 and MCRS1, whose expression is correlated with MYCN in WT samples and several of these are known for their own oncogenic potential. Conclusions The strongly elevated risk of relapse associated with mutant MYCN and MAX or elevated MYCN expression corroborates their role in WT oncogenesis. Together with the newly identified co-expressed interactors they expand the range of potential biomarkers for WT stratification and targeting, especially for high-risk WT.


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