scholarly journals The molecular basis of transient heme-protein interactions: analysis, concept and implementation

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Amelie Wißbrock ◽  
Ajay Abisheck Paul George ◽  
Hans Henning Brewitz ◽  
Toni Kühl ◽  
Diana Imhof
Keyword(s):  
Protein Interactions ◽  
Molecular Basis ◽  
Bacterial Infections ◽  
Specific Binding ◽  
Heme Protein ◽  
Future Research ◽  
Heme Binding ◽  
Prosthetic Group ◽  
Binding Behavior ◽  
Depth Analysis

Abstract Deviant levels of available heme and related molecules can result from pathological situations such as impaired heme biosynthesis or increased hemolysis as a consequence of vascular trauma or bacterial infections. Heme-related biological processes are affected by these situations, and it is essential to fully understand the underlying mechanisms. While heme has long been known as an important prosthetic group of various proteins, its function as a regulatory and signaling molecule is poorly understood. Diseases such as porphyria are caused by impaired heme metabolism, and heme itself might be used as a drug in order to downregulate its own biosynthesis. In addition, heme-driven side effects and symptoms emerging from heme-related pathological conditions are not fully comprehended and thus impede adequate medical treatment. Several heme-regulated proteins have been identified in the past decades, however, the molecular basis of transient heme-protein interactions remains to be explored. Herein, we summarize the results of an in-depth analysis of heme binding to proteins, which revealed specific binding modes and affinities depending on the amino acid sequence. Evaluating the binding behavior of a plethora of heme-peptide complexes resulted in the implementation of a prediction tool (SeqD-HBM) for heme-binding motifs, which eventually led and will perspectively lead to the identification and verification of so far unknown heme-regulated proteins. This systematic approach resulted in a broader picture of the alternative functions of heme as a regulator of proteins. However, knowledge on heme regulation of proteins is still a bottomless barrel that leaves much scope for future research and development.

Recent Advances on the Semi-Supervised Learning for Long Non-Coding RNA-Protein Interactions Prediction: A Review

2020 ◽  
Vol 27 (5) ◽  
pp. 385-391
Author(s):  
Lin Zhong ◽  
Zhong Ming ◽  
Guobo Xie ◽  
Chunlong Fan ◽  
Xue Piao
Keyword(s):  
Supervised Learning ◽  
Protein Interactions ◽  
Computational Models ◽  
Prediction Models ◽  
Chromatin Modification ◽  
Computational Prediction ◽  
Human Diseases ◽  
Future Research ◽  
Non Coding Rna ◽  
Long Non Coding Rna

: In recent years, more and more evidence indicates that long non-coding RNA (lncRNA) plays a significant role in the development of complex biological processes, especially in RNA progressing, chromatin modification, and cell differentiation, as well as many other processes. Surprisingly, lncRNA has an inseparable relationship with human diseases such as cancer. Therefore, only by knowing more about the function of lncRNA can we better solve the problems of human diseases. However, lncRNAs need to bind to proteins to perform their biomedical functions. So we can reveal the lncRNA function by studying the relationship between lncRNA and protein. But due to the limitations of traditional experiments, researchers often use computational prediction models to predict lncRNA protein interactions. In this review, we summarize several computational models of the lncRNA protein interactions prediction base on semi-supervised learning during the past two years, and introduce their advantages and shortcomings briefly. Finally, the future research directions of lncRNA protein interaction prediction are pointed out.

Computer-aided structural and molecular insights into the mechanisms by which Pseudouridimycin (PUM) disrupts cleft extension in bacterial RNA polymerase to block DNA entry and exit

2020 ◽  
Vol 17 ◽  
Author(s):  
Ali H. Rabbad ◽  
Fisayo A. Olotu ◽  
Mahmoud E. Soliman
Keyword(s):  
Rna Polymerase ◽  
Bacterial Infections ◽  
Entry And Exit ◽  
Dynamic Binding ◽  
Binding Behavior ◽  
Bacterial Rna ◽  
Nucleotide Addition ◽  
Switch Regions ◽  
Cleft Extension ◽  
Key Residues

Background: The ability of Pseudouridimycin (PUM) to occupy the nucleotide addition site of bacterial RNA Polymerase (RNAP) underlies its inhibitory potency as previously reported. PUM has gained high research interest as a broad-spectrum nucleoside analog that has demonstrated exciting potentials in treating drug-resistant bacterial infections. Objective: Herein, we identified, for the first time, a novel complementary mechanism by which PUM elicits its inhibitory effects on bacterial RNAP. Methods: The dynamic binding behavior of PUM to bacterial RNAP was studied using various dynamic analyses approaches. Results and Discussion: Findings revealed that in addition to occupying the nucleotide addition site, PUM also interrupts the unimpeded entry and exit of DNA by reducing the mechanistic extension of the RNAP cleft and perturbing the primary conformations of the switch regions. Moreover, PUM binding reduced the distances between key residues in the β and β’ subunits that extend to accommodate the DNA. Conclusion: This study’s findings present structural insights that would contribute to the structure-based design of potent and selective PUM inhibitors.

scholarly journals Structural and Functional Remodeling of Mitochondria in Cardiac Diseases

2021 ◽  
Vol 22 (8) ◽  
pp. 4167
Author(s):  
Xiaonan Sun ◽  
Jalen Alford ◽  
Hongyu Qiu
Keyword(s):  
Regulatory Network ◽  
Molecular Basis ◽  
Therapeutic Potential ◽  
Research Direction ◽  
Future Research ◽  
Cardiac Diseases ◽  
Functional Remodeling ◽  
Underlying Mechanisms ◽  
Mitochondrial Remodeling ◽  
Normal Cellular Function

Mitochondria undergo structural and functional remodeling to meet the cell demand in response to the intracellular and extracellular stimulations, playing an essential role in maintaining normal cellular function. Merging evidence demonstrated that dysregulation of mitochondrial remodeling is a fundamental driving force of complex human diseases, highlighting its crucial pathophysiological roles and therapeutic potential. In this review, we outlined the progress of the molecular basis of mitochondrial structural and functional remodeling and their regulatory network. In particular, we summarized the latest evidence of the fundamental association of impaired mitochondrial remodeling in developing diverse cardiac diseases and the underlying mechanisms. We also explored the therapeutic potential related to mitochondrial remodeling and future research direction. This updated information would improve our knowledge of mitochondrial biology and cardiac diseases’ pathogenesis, which would inspire new potential strategies for treating these diseases by targeting mitochondria remodeling.

scholarly journals Power-law behavior of transcription factor dynamics at the single-molecule level implies a continuum affinity model

2021 ◽  
Author(s):  
David A Garcia ◽  
Gregory Fettweis ◽  
Diego M Presman ◽  
Ville Paakinaho ◽  
Christopher Jarzynski ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Single Molecule ◽  
Power Law ◽  
Dwell Time ◽  
Specific Binding ◽  
Power Law Distribution ◽  
Single Molecule Level ◽  
Binding Behavior ◽  
Chromatin Template ◽  
Nuclear Domains

Abstract Single-molecule tracking (SMT) allows the study of transcription factor (TF) dynamics in the nucleus, giving important information regarding the diffusion and binding behavior of these proteins in the nuclear environment. Dwell time distributions obtained by SMT for most TFs appear to follow bi-exponential behavior. This has been ascribed to two discrete populations of TFs—one non-specifically bound to chromatin and another specifically bound to target sites, as implied by decades of biochemical studies. However, emerging studies suggest alternate models for dwell-time distributions, indicating the existence of more than two populations of TFs (multi-exponential distribution), or even the absence of discrete states altogether (power-law distribution). Here, we present an analytical pipeline to evaluate which model best explains SMT data. We find that a broad spectrum of TFs (including glucocorticoid receptor, oestrogen receptor, FOXA1, CTCF) follow a power-law distribution of dwell-times, blurring the temporal line between non-specific and specific binding, suggesting that productive binding may involve longer binding events than previously believed. From these observations, we propose a continuum of affinities model to explain TF dynamics, that is consistent with complex interactions of TFs with multiple nuclear domains as well as binding and searching on the chromatin template.

scholarly journals Interaction of Temporin-L Analogues with the E. coli FtsZ Protein

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 704
Author(s):  
Angela Di Somma ◽  
Carolina Canè ◽  
Antonio Moretta ◽  
Angela Duilio
Keyword(s):  
Protein Interactions ◽  
Bacterial Infections ◽  
Antibacterial Properties ◽  
Bacterial Cell Division ◽  
Structural Determinants ◽  
E Coli ◽  
Functional Studies ◽  
Division Process ◽  
Z Ring ◽  
Peptide Complexes

The research of new therapeutic agents to fight bacterial infections has recently focused on the investigation of antimicrobial peptides (AMPs), the most common weapon that all organisms produce to prevent invasion by external pathogens. Among AMPs, the amphibian Temporins constitute a well-known family with high antibacterial properties against Gram-positive and Gram-negative bacteria. In particular, Temporin-L was shown to affect bacterial cell division by inhibiting FtsZ, a tubulin-like protein involved in the crucial step of Z-ring formation at the beginning of the division process. As FtsZ represents a leading target for new antibacterial compounds, in this paper we investigated in detail the interaction of Temporin L with Escherichia coli FtsZ and designed two TL analogues in an attempt to increase peptide-protein interactions and to better understand the structural determinants leading to FtsZ inhibition. The results demonstrated that the TL analogues improved their binding to FtsZ, originating stable protein-peptide complexes. Functional studies showed that both peptides were endowed with a high capability of inhibiting both the enzymatic and polymerization activities of the protein. Moreover, the TL analogues were able to inhibit bacterial growth at low micromolar concentrations. These observations may open up the way to the development of novel peptide or peptidomimetic drugs tailored to bind FtsZ, hampering a crucial process of bacterial life that might be proposed for future pharmaceutical applications.

Social appreciation for the improvement of tourism management of 20th-century heritage: a methodological proposal

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Gema Ramírez-Guerrero ◽  
Javier García-Onetti ◽  
Juan Adolfo Chica-Ruiz ◽  
Manuel Arcíla-Garrido
Keyword(s):  
20Th Century ◽  
Management Tool ◽  
Future Research ◽  
Analysis Tool ◽  
Content Type ◽  
Cultural Assets ◽  
Current State ◽  
The Social ◽  
Depth Analysis ◽  
The Creation

Purpose This paper attempts to fill the gap that exists in research regarding 20th-century heritage and its social appreciation. The purpose of this paper is to explore different ways of evaluating the heritage value and tourism potential and to propose an innovative model validated in the Zarzuela Hippodrome as an example of cultural asset from 20th century with important economic, social, cultural, aesthetic and architectural aspects. Design/methodology/approach This study opted for an interpretation of heritage from an ecosystem, integrating and global paradigm, understanding the asset as a set of resources that interact with each other, generating a common and enriched tourist experience among all the elements that make it up. From this perspective, it is conceived that by modifying one of the elements, the whole (tourist) ecosystem will be equally influenced. On the other side, it was incorporated non-parametric techniques based on the implementation of surveys for the validation of the tool to the case study of the Zarzuela hippodrome. Findings The results suggest that the hippodrome's internal values have been evaluated very positively, while its external values are low. Through this study, the paper has identified several weaknesses that impede its functioning as a viable “tourist product.” The distance from the city center, the lack of available information and the scarce diffusion and tourism promotion are its main weaknesses. The proposed analysis tool reveals the importance of the active participation of visitors to evaluate cultural assets through the combination of aspects related to the conservation of cultural assets and, in turn, elements that encourage their commodification as tourist products, break down barriers between these two disciplines. Research limitations/implications The management tool proposed in this study can be used to underpin the creation of tourism experiences in cultural or heritage assets by diagnosing the current state of its tourist potential, quantifying its value in relation to the visitors’ perception and making visible those problematic aspects to develop actions to solve them. Although the present study is support for future research, as well as for improving the marketing of heritage in tourist settings, an in-depth analysis of the technical elements of heritage, as well as of its intervention (if applicable), will be necessary for the managers who want to use the tool. Social implications One of the most differentiating characteristics between the construction typology of 20th-century historical buildings is perhaps the scarcity of decorative ornamentation, with exposed concrete being the main surface coating. Many of these constructions have an important cultural and historical relevance, however, the social perception, as regards its consideration as architectural and artistic heritage seems to reflect discordant aspects. This study provides support as a decision-making tool to determine the existing valuation of a building and how to enhance it. Originality/value This study takes steps toward the creation of a model that supports decision-makers and owners of cultural assets through a measurement system that makes it possible to quantify and determine the current state of tourism use through the social evaluation of heritage criteria. It defines which are the elements that favor the resilience of the property or, on the contrary, which are those that undermine its enhancement.

Raw milk collection in Ireland: insights into the challenges facing the industry

2022 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Seán O'Callaghan ◽  
Declan O. Connor ◽  
David Goulding
Keyword(s):  
Positive Impact ◽  
Environmental Issues ◽  
Raw Milk ◽  
Transportation Costs ◽  
Transportation Infrastructure ◽  
Environmental Cost ◽  
Future Research ◽  
Content Type ◽  
Depth Analysis ◽  
Transportation Emissions

PurposeThis paper provides insights into national practices used to schedule, collect and manage the transportation infrastructure of raw milk by Irish processors.Design/methodology/approachA survey was designed and distributed to 14 processors, collecting details regarding suppliers, seasonality, costs per litre, planning, processing sites and emissions related to milk collection.FindingsIrish raw milk transportation costs €95 million per annum, with an average weighted cost of 1.1 cents per litre. Primary route clustering of suppliers is based on farm location. Typically, collections employ forty-eight-hour rotas. Just three of the processors reported transportation emissions data. A disjointed approach to the adoption of scheduling and transportation technology was revealed.Research limitations/implicationsGiven the broad scope of the survey covering financial, operational and environmental aspects of milk collection, it was challenging to find a single representative such as a transport manager who could be tasked with responding to the entire survey. Future research may consider a more focused interview-based approach with the various stakeholders to provide a more in-depth analysis.Practical implicationsProcessors can gain an improved understanding of diversified milk collection methods. The research supports policymakers in considering environmental issues related to milk transportation. Costs could be reduced if transportation was better managed collectively with benefits accruing to the industry, suppliers and wider rural community. Stakeholders will need to address aspects of responsibility concerning environmental issues going forward.Social implicationsIn this paper the authors recognise the environmental cost of milk collection. By improving the transportation infrastructure, this will have a positive impact on society in general.Originality/valueThe paper highlights the unique challenges and extends present knowledge in relation to milk collection; thus, this paves the way for new approaches to raw milk transportation.

Genetic regulation of nitrogen metabolism in the fungi

1997 ◽  
Vol 61 (1) ◽  
pp. 17-32
Author(s):  
G A Marzluf
Keyword(s):  
Nitrogen Metabolism ◽  
Protein Interactions ◽  
Fungal Pathogens ◽  
Metabolic Regulation ◽  
Specific Binding ◽  
Genetic Regulation ◽  
Nitrogen Sources ◽  
Specific Protein ◽  
Genes Encoding ◽  
Gata Family

In the fungi, nitrogen metabolism is controlled by a complex genetic regulatory circuit which ensures the preferential use of primary nitrogen sources and also confers the ability to use many different secondary nitrogen sources when appropriate. Most structural genes encoding nitrogen catabolic enzymes are subject to nitrogen catabolite repression, mediated by positive-acting transcription factors of the GATA family of proteins. However, certain GATA family members, such as the yeast DAL80 factor, act negatively to repress gene expression. Selective expression of the genes which encode enzymes for the metabolism of secondary nitrogen sources is often achieved by induction, mediated by pathway-specific factors, many of which have a GAL4-like C6/Zn2 DNA binding domain. Regulation within the nitrogen circuit also involves specific protein-protein interactions, as exemplified by the specific binding of the negative-acting NMR protein with the positive-acting NIT2 protein of Neurospora crassa. Nitrogen metabolic regulation appears to play a significant role in the pathogenicity of certain animal and plant fungal pathogens.

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.

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