scholarly journals A [6+4]-cycloaddition adduct is the biosynthetic intermediate in streptoseomycin biosynthesis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kai Biao Wang ◽  
Wen Wang ◽  
Bo Zhang ◽  
Xin Wang ◽  
Yu Chen ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Biosynthetic Gene Cluster ◽  
Cope Rearrangement ◽  
Biosynthetic Gene ◽  
Protein Protein Interactions ◽  
Ether Bridge ◽  
Tricyclic Core ◽  
Bona Fide ◽  
Heterodimeric Complex ◽  
Direct Hydroxylation

AbstractStreptoseomycin (STM, 1) is a bacterial macrolactone that has a unique 5/14/10/6/6-pentacyclic ring with an ether bridge. We have previously identified the biosynthetic gene cluster for 1 and characterized StmD as [6 + 4]- and [4 + 2]-bispericyclase that catalyze a reaction leading to both 6/10/6- and 10/6/6-tricyclic adducts (6 and 7). The remaining steps, especially how to install and stabilize the required 10/6/6-tricyclic core for downstream modifications, remain unknown. In this work, we have identified three oxidoreductases that fix the required 10/6/6-tryciclic core. A pair of flavin-dependent oxidoreductases, StmO1 and StmO2, catalyze the direct hydroxylation at [6 + 4]-adduct (6). Subsequently, a spontaneous [3,3]-Cope rearrangement and an enol-ketone tautomerization result in the formation of 10/6/6-tricyclic intermediate 12b, which can be further converted to a stable 10/6/6-tricyclic alcohol 11 through a ketoreduction by StmK. Crystal structure of the heterodimeric complex NtfO1-NtfO2, homologues of StmO1-StmO2 with equivalent function, reveals protein-protein interactions. Our results demonstrate that the [6 + 4]-adduct instead of [4 + 2]-adduct is the bona fide biosynthetic intermediate.

scholarly journals PIPINO: A Software Package to Facilitate the Identification of Protein-Protein Interactions from Affinity Purification Mass Spectrometry Data

2016 ◽  
Vol 2016 ◽  
pp. 1-13
Author(s):  
Stefan Kalkhof ◽  
Stefan Schildbach ◽  
Conny Blumert ◽  
Friedemann Horn ◽  
Martin von Bergen ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Protein Interactions ◽  
Isotope Labeling ◽  
Affinity Purification ◽  
Interaction Network ◽  
Mass Spectrometry Data ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Binding Behavior ◽  
Bona Fide

The functionality of most proteins is regulated by protein-protein interactions. Hence, the comprehensive characterization of the interactome is the next milestone on the path to understand the biochemistry of the cell. A powerful method to detect protein-protein interactions is a combination of coimmunoprecipitation or affinity purification with quantitative mass spectrometry. Nevertheless, both methods tend to precipitate a high number of background proteins due to nonspecific interactions. To address this challenge the software Protein-Protein-Interaction-Optimizer (PIPINO) was developed to perform an automated data analysis, to facilitate the selection of bona fide binding partners, and to compare the dynamic of interaction networks. In this study we investigated the STAT1 interaction network and its activation dependent dynamics. Stable isotope labeling by amino acids in cell culture (SILAC) was applied to analyze the STAT1 interactome after streptavidin pull-down of biotagged STAT1 from human embryonic kidney 293T cells with and without activation. Starting from more than 2,000 captured proteins 30 potential STAT1 interaction partners were extracted. Interestingly, more than 50% of these were already reported or predicted to bind STAT1. Furthermore, 16 proteins were found to affect the binding behavior depending on STAT1 phosphorylation such as STAT3 or the importin subunits alpha 1 and alpha 6.

Tyrosine-O-sulfation is a widespread affinity enhancer among thrombin interactors

2022 ◽  
Author(s):  
Jorge Ripoll-Rozada ◽  
Joshua W. C. Maxwell ◽  
Richard J. Payne ◽  
Pedro José Barbosa Pereira
Keyword(s):  
Protein Interactions ◽  
Secretory Pathway ◽  
Serine Proteinase ◽  
Blood Feeding ◽  
Thrombin Inhibitor ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Human Fibrinogen ◽  
Clotting Cascade ◽  
Bona Fide

Tyrosine-O-sulfation is a common post-translational modification (PTM) of proteins following the cellular secretory pathway. First described in human fibrinogen, tyrosine-O-sulfation has long been associated with the modulation of protein–protein interactions in several physiological processes. A number of relevant interactions for hemostasis are largely dictated by this PTM, many of which involving the serine proteinase thrombin (FIIa), a central player in the blood-clotting cascade. Tyrosine sulfation is not limited to endogenous FIIa ligands and has also been found in hirudin, a well-known and potent thrombin inhibitor from the medicinal leech, Hirudo medicinalis. The discovery of hirudin led to successful clinical application of analogs of leech-inspired molecules, but also unveiled several other natural thrombin-directed anticoagulant molecules, many of which undergo tyrosine-O-sulfation. The presence of this PTM has been shown to enhance the anticoagulant properties of these peptides from a range of blood-feeding organisms, including ticks, mosquitos and flies. Interestingly, some of these molecules display mechanisms of action that mimic those of thrombin's bona fide substrates.

scholarly journals Lipid signaling to membrane proteins: From second messengers to membrane domains and adapter-free endocytosis

2018 ◽  
Vol 150 (2) ◽  
pp. 211-224 ◽  
Author(s):  
Donald W. Hilgemann ◽  
Gucan Dai ◽  
Anthony Collins ◽  
Vincenzo Larricia ◽  
Simona Magi ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Second Messengers ◽  
Surface Membrane ◽  
Short Review ◽  
Lipid Signaling ◽  
Membrane Domains ◽  
Protein Protein Interactions ◽  
Protein Membrane ◽  
Bona Fide ◽  
And Control

Lipids influence powerfully the function of ion channels and transporters in two well-documented ways. A few lipids act as bona fide second messengers by binding to specific sites that control channel and transporter gating. Other lipids act nonspecifically by modifying the physical environment of channels and transporters, in particular the protein–membrane interface. In this short review, we first consider lipid signaling from this traditional viewpoint, highlighting innumerable Journal of General Physiology publications that have contributed to our present understanding. We then switch to our own emerging view that much important lipid signaling occurs via the formation of membrane domains that influence the function of channels and transporters within them, promote selected protein–protein interactions, and control the turnover of surface membrane.

scholarly journals The nematode homologue of Mediator complex subunit 28, F28F8.5, is a critical regulator of C. elegans development

2016 ◽  
Author(s):  
Markéta Kostrouchová ◽  
David Kostrouch ◽  
Ahmed A Chughtai ◽  
Filip Kaššák ◽  
Jan P. Novotný ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Protein Interactions ◽  
Structural Proteins ◽  
Mediator Complex ◽  
Cytoplasmic Localization ◽  
Protein Protein Interactions ◽  
C Elegans ◽  
Evolutionarily Conserved ◽  
Nuclear Events ◽  
Bona Fide

The evolutionarily conserved Mediator complex is a critical player in regulating transcription. Comprised of approximately two dozen proteins, Mediator integrates diverse regulatory signals through direct protein-protein interactions that, in turn, modulate the influence of Mediator on RNA Polymerase II activity. One Mediator subunit, MED28, is known to interact with cytoplasmic structural proteins, providing a potential direct link between cytoplasmic dynamics and the control of gene transcription. Although identified in many animals and plants, MED28 is not present in yeast; no bona fide MED28 has been described previously in C. elegans. Here, we identify bioinformatically F28F8.5, an uncharacterized predicted protein, as the nematode homologue of MED28. As in other metazoa, F28F8.5 has dual nuclear and cytoplasmic localization and plays critical roles in the regulation of development. F28F8.5 is a vital gene and its null mutants have severely malformed gonads and do not reproduce. Our results indicate that F28F8.5 is a homologue of MED28 and suggest that the potential to link cytoplasmic and nuclear events is conserved between MED28 vertebrate and nematode homologues.

How Cancer Cells Resist Chemotherapy: Design and Development of Drugs Targeting Protein-Protein Interactions

2019 ◽  
Vol 19 (6) ◽  
pp. 394-412 ◽  
Author(s):  
Vadim V. Tarasov ◽  
Vladimir N. Chubarev ◽  
Ghulam Md Ashraf ◽  
Samira A. Dostdar ◽  
Alexander V. Sokolov ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Clinical Outcome ◽  
Cancer Cells ◽  
Protein Interactions ◽  
Resistance Mechanisms ◽  
Protein Protein Interactions ◽  
Treatment Regimens ◽  
Pubmed Search ◽  
Bona Fide ◽  
Improve Clinical Outcome

Background:Resistance toward chemotherapeutics is one of the main obstacles on the way to effective cancer treatment. Personalization of chemotherapy could improve clinical outcome. However, despite preclinical significance, most of the potential markers have failed to reach clinical practice partially due to the inability of numerous studies to estimate the marker’s impact on resistance properly.Objective:The analysis of drug resistance mechanisms to chemotherapy in cancer cells, and the proposal of study design to identify bona fide markers.Methods:A review of relevant papers in the field. A PubMed search with relevant keywords was used to gather the data. An example of a search request: drug resistance AND cancer AND paclitaxel.Results:We have described a number of drug resistance mechanisms to various chemotherapeutics, as well as markers to underlie the phenomenon. We also proposed a model of a rational-designed study, which could be useful in determining the most promising potential biomarkers.Conclusion:Taking into account the most reasonable biomarkers should dramatically improve clinical outcome by choosing the suitable treatment regimens. However, determining the leading biomarkers, as well as validating of the model, is a work for further investigations.

scholarly journals The nematode homologue of Mediator complex subunit 28, F28F8.5, is a critical regulator of C. elegans development

2016 ◽  
Author(s):  
Markéta Kostrouchová ◽  
David Kostrouch ◽  
Ahmed A Chughtai ◽  
Filip Kaššák ◽  
Jan P. Novotný ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Protein Interactions ◽  
Structural Proteins ◽  
Mediator Complex ◽  
Cytoplasmic Localization ◽  
Protein Protein Interactions ◽  
C Elegans ◽  
Evolutionarily Conserved ◽  
Nuclear Events ◽  
Bona Fide

The evolutionarily conserved Mediator complex is a critical player in regulating transcription. Comprised of approximately two dozen proteins, Mediator integrates diverse regulatory signals through direct protein-protein interactions that, in turn, modulate the influence of Mediator on RNA Polymerase II activity. One Mediator subunit, MED28, is known to interact with cytoplasmic structural proteins, providing a potential direct link between cytoplasmic dynamics and the control of gene transcription. Although identified in many animals and plants, MED28 is not present in yeast; no bona fide MED28 has been described previously in C. elegans. Here, we identify bioinformatically F28F8.5, an uncharacterized predicted protein, as the nematode homologue of MED28. As in other metazoa, F28F8.5 has dual nuclear and cytoplasmic localization and plays critical roles in the regulation of development. F28F8.5 is a vital gene and its null mutants have severely malformed gonads and do not reproduce. Our results indicate that F28F8.5 is a homologue of MED28 and suggest that the potential to link cytoplasmic and nuclear events is conserved between MED28 vertebrate and nematode homologues.

scholarly journals The nematode homologue of Mediator complex subunit 28, F28F8.5, is a critical regulator ofC. elegansdevelopment

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3390
Author(s):  
Markéta Kostrouchová ◽  
David Kostrouch ◽  
Ahmed A. Chughtai ◽  
Filip Kaššák ◽  
Jan P. Novotný ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Protein Interactions ◽  
Structural Proteins ◽  
Mediator Complex ◽  
Cytoplasmic Localization ◽  
Protein Protein Interactions ◽  
Evolutionarily Conserved ◽  
Nuclear Events ◽  
Bona Fide ◽  
Null Mutants

The evolutionarily conserved Mediator complex is a critical player in regulating transcription. Comprised of approximately two dozen proteins, the Mediator integrates diverse regulatory signals through direct protein-protein interactions that, in turn, modulate the influence of Mediator on RNA Polymerase II activity. One Mediator subunit, MED28, is known to interact with cytoplasmic structural proteins, providing a potential direct link between cytoplasmic dynamics and the control of gene transcription. Although identified in many animals and plants, MED28 is not present in yeast; no bona fide MED28 has been described previously inCaenorhabditis elegans.Here, we identify bioinformatically F28F8.5, an uncharacterized predicted protein, as the nematode homologue of MED28. As in other Metazoa, F28F8.5 has dual nuclear and cytoplasmic localization and plays critical roles in the regulation of development.F28F8.5is a vital gene and its null mutants have severely malformed gonads and do not reproduce. F28F8.5 interacts on the protein level with the Mediator subunits MDT-6 and MDT-30. Our results indicate that F28F8.5 is an orthologue of MED28 and suggest that the potential to link cytoplasmic and nuclear events is conserved between MED28 vertebrate and nematode orthologues.

scholarly journals The nematode homologue of Mediator complex subunit 28, F28F8.5, is a critical regulator of C. elegans development

2016 ◽  
Author(s):  
Markéta Kostrouchová ◽  
David Kostrouch ◽  
Ahmed A Chughtai ◽  
Filip Kaššák ◽  
Jan P. Novotný ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Protein Interactions ◽  
Structural Proteins ◽  
Mediator Complex ◽  
Cytoplasmic Localization ◽  
Protein Protein Interactions ◽  
C Elegans ◽  
Evolutionarily Conserved ◽  
Nuclear Events ◽  
Bona Fide

The evolutionarily conserved Mediator complex is a critical player in regulating transcription. Comprised of approximately two dozen proteins, Mediator integrates diverse regulatory signals through direct protein-protein interactions that, in turn, modulate the influence of Mediator on RNA Polymerase II activity. One Mediator subunit, MED28, is known to interact with cytoplasmic structural proteins, providing a potential direct link between cytoplasmic dynamics and the control of gene transcription. Although identified in many animals and plants, MED28 is not present in yeast; no bona fide MED28 has been described previously in C. elegans. Here, we identify bioinformatically F28F8.5, an uncharacterized predicted protein, as the nematode homologue of MED28. As in other metazoa, F28F8.5 has dual nuclear and cytoplasmic localization and plays critical roles in the regulation of development. F28F8.5 is a vital gene and its null mutants have severely malformed gonads and do not reproduce. Our results indicate that F28F8.5 is a homologue of MED28 and suggest that the potential to link cytoplasmic and nuclear events is conserved between MED28 vertebrate and nematode homologues.

scholarly journals The Scope of Astrocyte Elevated Gene-1/Metadherin (AEG-1/MTDH) in Cancer Clinicopathology: A Review

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 308
Author(s):  
Maheen Khan ◽  
Devanand Sarkar
Keyword(s):  
Mouse Models ◽  
Protein Interactions ◽  
Rna Binding ◽  
Protein Protein Interactions ◽  
Vast Number ◽  
Cancer Hallmarks ◽  
Model Studies ◽  
Oncogenic Pathways ◽  
Bona Fide ◽  
Solid Foundation

Since its initial cloning in 2002, a plethora of studies in a vast number of cancer indications, has strongly established AEG-1 as a bona fide oncogene. In all types of cancer cells, overexpression and knockdown studies have demonstrated that AEG-1 performs a seminal role in regulating proliferation, invasion, angiogenesis, metastasis and chemoresistance, the defining cancer hallmarks, by a variety of mechanisms, including protein-protein interactions activating diverse oncogenic pathways, RNA-binding promoting translation and regulation of inflammation, lipid metabolism and tumor microenvironment. These findings have been strongly buttressed by demonstration of increased tumorigenesis in tissue-specific AEG-1 transgenic mouse models, and profound resistance of multiple types of cancer development and progression in total and conditional AEG-1 knockout mouse models. Additionally, clinicopathologic correlations of AEG-1 expression in a diverse array of cancers establishing AEG-1 as an independent biomarker for highly aggressive, chemoresistance metastatic disease with poor prognosis have provided a solid foundation to the mechanistic and mouse model studies. In this review a comprehensive analysis of the current and up-to-date literature is provided to delineate the clinical significance of AEG-1 in cancer highlighting the commonality of the findings and the discrepancies and discussing the implications of these observations.

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