Mol Biosyst [JOURNAL]
Sun
200 papers
Impact of phenylalanines outside the dimer interface on phosphotriesterase stability and function.
Olsen AJ, Halvorsen LA, Yang CY … +5 more , Barak Ventura R, Yin L, Renfrew PD, Bonneau R, Montclare JK
Mol Biosyst · 2017 Sep · PMID 28817149 · Publisher ↗
We explore the significance of phenylalanine outside of the phosphotriesterase (PTE) dimer interface through mutagenesis studies and computational modeling. Previous studies have demonstrated that the residue-specific in...
We explore the significance of phenylalanine outside of the phosphotriesterase (PTE) dimer interface through mutagenesis studies and computational modeling. Previous studies have demonstrated that the residue-specific incorporation of para-fluorophenylalanine (pFF) into PTE improves stability, suggesting the importance of phenylalanines in stabilization of the dimer. However, this comes at a cost of decreased solubility due to pFF incorporation into other parts of the protein. Motivated by this, eight single solvent-exposed phenylalanine mutants are evaluated viarosetta and good correspondence between experiments and these predictions is observed. Three residues, F304, F327, and F335, appear to be important for PTE activity and stability, even though they do not reside in the dimer interface region or active site. While the remaining mutants do not significantly affect structure or activity, one variant, F306L, reveals improved activity at ambient and elevated temperatures. These studies provide further insight into role of these residues on PTE function and stability.
Dissection of the module network implementation "LemonTree": enhancements towards applications in metagenomics and translation in autoimmune maladies.
Lu Y, Zhou X, Nardini C
Mol Biosyst · 2017 Sep · PMID 28809429 · Publisher ↗
Under the current deluge of omics, module networks distinctively emerge as methods capable of not only identifying inherently coherent groups (modules), thus reducing dimensionality, but also hypothesizing cause-effect r...
Under the current deluge of omics, module networks distinctively emerge as methods capable of not only identifying inherently coherent groups (modules), thus reducing dimensionality, but also hypothesizing cause-effect relationships between modules and their regulators. Module networks were first designed in the transcriptomic era and further exploited in the multi-omic context to assess (for example) miRNA regulation of gene expression. Despite a number of available implementations, expansion of module networks to other omics is constrained by a limited characterization of the solutions' (modules plus regulators) accuracy and stability - an immediate need for the better characterization of molecular biology complexity in silico. We hence carefully assessed for LemonTree - a popular and open source module network implementation - the dependency of the software performances (sensitivity, specificity, false discovery rate, solutions' stability) on the input parameters and on the data quality (sample size, expression noise) based on synthetic and real data. In the process, we uncovered and fixed an issue in the code for the regulator assignment procedure. We concluded this evaluation with a table of recommended parameter settings. Finally, we applied these recommended settings to gut-intestinal metagenomic data from rheumatoid arthritis patients, to characterize the evolution of the gut-intestinal microbiome under different pharmaceutical regimens (methotrexate and prednisone) and we inferred innovative clinical recommendations with therapeutic potential, based on the computed module network.
Quantitative investigation of MDA-MB-231 breast cancer cell motility: dependence on epidermal growth factor concentration and its gradient.
Islam T, Resat H
Mol Biosyst · 2017 Sep · PMID 28799616 · Full text
Enhanced cell motility is one of the primary features of cancer. Accumulated evidence demonstrates that Epidermal Growth Factor Receptor (EGFR) mediated pathways play an important role in breast cancer cell proliferation...
Enhanced cell motility is one of the primary features of cancer. Accumulated evidence demonstrates that Epidermal Growth Factor Receptor (EGFR) mediated pathways play an important role in breast cancer cell proliferation and migration. We have quantified the MDA-MB-231 breast cancer cell migration in response to the stimulation of EGFR pathways with their ligand EGF to determine how the cell motility of MDA-MB-231 cells depends on the ligand concentration and gradient. Analysis at the single cell level combined with mathematical modeling and the ability to vary the ligand concentration and gradients locally using microfluidic devices allowed us to separate the unique contributions of ligand concentration and ligand gradient to cell motility. We tracked the motility of 6600 cells individually using time lapse imaging under varying EGF stimulation conditions. Trajectory analysis of the tracked cells using non-linear multivariate regression models showed that: (i) cell migration of MDA-MB-231 breast cancer cells depends on the ligand gradient but not on the ligand concentration. This observation was valid for both the total (direction independent) and directed (along gradient direction) cell velocities. Although the dependence of the directed motility on ligand gradient is to be expected, the dependence of the total velocity solely on ligand gradient was an unexpected novel observation. (ii) Enhancement of the motilities of individual cells in a population upon exposure to the ligand was highly heterogeneous, and only a very small percentage of cells responded strongly to the external stimuli. Separating out the non-responding cells using quantitative analysis of individual cell motilities enabled us to establish that enhanced motility of the responding cells indeed increases monotonically with increasing EGF gradient. (iii) A large proportion of cells in a population were unresponsive to ligand stimulation, and their presence introduced considerable random intrinsic variability to the observations. This indicated that studying cell motilities at the individual cell level is necessary to better capture the biological reality and that population averaging methods should be avoided. Studying motilities at the individual cell level is particularly important to understand the biological processes that are possibly driven by the action of a small portion of cells in a population, such as metastasis. We discuss the implications of our results on the total and chemotactic movement of cancer cells in the tumor microenvironment.
Proximity aptasensor for protein detection based on an enzyme-free amplification strategy.
Yang D, Tang Y, Guo Z … +2 more , Chen X, Miao P
Mol Biosyst · 2017 Sep · PMID 28796267 · Publisher ↗
A novel electrochemical aptasensor for the detection of trace protein is proposed based on proximity binding-induced strand displacement and hybridization chain reaction. This method is proven to be highly selective and...
A novel electrochemical aptasensor for the detection of trace protein is proposed based on proximity binding-induced strand displacement and hybridization chain reaction. This method is proven to be highly selective and has potential practical utility, and offers new opportunities for the convenient detection of proteins with an enzyme-free amplification process.
Role of GARP in the activation of latent TGF-β1.
Stockis J, Dedobbeleer O, Lucas S
Mol Biosyst · 2017 Sep · PMID 28795730 · Publisher ↗
TGF-β1, 2 and 3 cytokines are involved in many cellular processes including cell proliferation, differentiation, migration and survival. Whereas TGF-β2 and 3 play important roles in embryonic development, TGF-β1 is mostl...
TGF-β1, 2 and 3 cytokines are involved in many cellular processes including cell proliferation, differentiation, migration and survival. Whereas TGF-β2 and 3 play important roles in embryonic development, TGF-β1 is mostly implicated in controlling immune responses after birth. The production of TGF-β1 is a tightly regulated process, occurring mostly at a post-translational level. Virtually all cells produce the latent, inactive form of TGF-β1. In latent TGF-β1, the mature TGF-β1 dimer is non-covalently associated to the Latency Associated Peptide, or LAP, which prevents binding to the TGF-β1 receptor. Activation of the cytokine implies release of mature TGF-β1 from LAP. Only a few cell types activate latent TGF-β1, via mechanisms that are cell type specific. Proteins such as integrins, proteases and thrombospondin-1 activate TGF-β1 in epithelial cells, fibroblasts and dendritic cells. More recently, the protein GARP was shown to be involved in TGF-β1 activation by regulatory T cells (Treg), a subset of CD4 T lymphocytes specialized in suppression of immune responses. GARP is a transmembrane protein that binds latent-TGF-β1 and tethers it on the Treg surface. The role of GARP was studied mostly in Tregs, and this was recently reviewed in L. Sun, H. Jin and H. Li, Oncotarget, 2016, 7, 42826-42836. However, GARP is also expressed in non-immune cells. This review focuses on the roles of GARP in latent TGF-β1 activation by immune and non-immune cells.
Restoring calcium homeostasis in diabetic cardiomyocytes: an investigation through mathematical modelling.
Das PN, Kumar A, Bairagi N … +1 more , Chatterjee S
Mol Biosyst · 2017 Sep · PMID 28795720 · Publisher ↗
Calcium homeostasis is a key factor in the regulation of cardiac excitation-contraction coupling. Calcium dynamics in cardiomyocytes is governed by ATP which depends on insulin dependent glucose concentration, via the gl...
Calcium homeostasis is a key factor in the regulation of cardiac excitation-contraction coupling. Calcium dynamics in cardiomyocytes is governed by ATP which depends on insulin dependent glucose concentration, via the glucose transporter type 4 (GLUT4) transporter. It would therefore be interesting to see how calcium dynamics changes in a cardiomyocyte under diabetic conditions. We proposed and analysed a four dimensional ordinary differential equation (ODE) model to capture the interdependency of calcium dynamics on glucose uptake and ATP generation. More specifically, we looked for the role of GLUT4, energy metabolism, L-type channels, RyR2 channels, SERCA2a pumps and leakage rate in the normal functioning of cardiomyocytes. To understand the system dynamics, we first obtained the stability and Hopf-bifurcation criteria of steady state and then through parameter perturbation we captured the role of different parameters in maintaining normal calcium oscillation (frequency 40 to 180 beats per minute and amplitude ≥0.4 μM) and hence normal cardiac function. We observed that any divergence in the GLUT4 activity (especially a decrease in the glucose uptake rate) might cause abnormal calcium oscillation, leading to cardiac dysfunction (CD). Our study finally hypothesizes that a regulated sarcoplasmic reticulum (SR) calcium flux could be a possible therapeutic strategy to maintain normal calcium dynamics in diabetic heart and to prevent possible CD.
Murine cutaneous leishmaniasis investigated by MALDI mass spectrometry imaging.
Negrão F, de O Rocha DF, Jaeeger CF … +3 more , Rocha FJS, Eberlin MN, Giorgio S
Mol Biosyst · 2017 Sep · PMID 28783195 · Publisher ↗
Imaging mass spectrometry (IMS) is recognized as a powerful tool to investigate the spatial distribution of untargeted or targeted molecules of a wide variety of samples including tissue sections. Leishmania is a protozo...
Imaging mass spectrometry (IMS) is recognized as a powerful tool to investigate the spatial distribution of untargeted or targeted molecules of a wide variety of samples including tissue sections. Leishmania is a protozoan parasite that causes different clinical manifestations in mammalian hosts. Leishmaniasis is a major public health risk in different continents and represents one of the most important neglected diseases. Cutaneous lesions from mice experimentally infected with Leishmania spp. were investigated by matrix-assisted laser desorption ionization MS using the SCiLS Lab software for statistical analysis. Being applied to cutaneous leishmaniasis (CL) for the first time, MALDI-IMS was used to search for peptides and low molecular weight proteins (2-10 kDa) as candidates for potential biomarkers. Footpad sections of Balb/c mice infected with (i) Leishmania amazonensis or (ii) Leishmania major were imaged. The comparison between healthy and infected skin highlighted a set of twelve possible biomarker proteins for L. amazonenis and four proteins for L. major. Further characterization of these proteins could reveal how these proteins act in pathology progression and confirm their values as biomarkers.
Protein intrinsic disorder negatively associates with gene age in different eukaryotic lineages.
Banerjee S, Chakraborty S
Mol Biosyst · 2017 Sep · PMID 28783193 · Publisher ↗
The emergence of new protein-coding genes in a specific lineage or species provides raw materials for evolutionary adaptations. Until recently, the biology of new genes emerging particularly from non-genic sequences rema...
The emergence of new protein-coding genes in a specific lineage or species provides raw materials for evolutionary adaptations. Until recently, the biology of new genes emerging particularly from non-genic sequences remained unexplored. Although the new genes are subjected to variable selection pressure and face rapid deletion, some of them become functional and are retained in the gene pool. To acquire functional novelties, new genes often get integrated into the pre-existing ancestral networks. However, the mechanism by which young proteins acquire novel interactions remains unanswered till date. Since structural orientation contributes hugely to the mode of proteins' physical interactions, in this regard, we put forward an interesting question - Do new genes encode proteins with stable folds? Addressing the question, we demonstrated that the intrinsic disorder inversely correlates with the evolutionary gene ages - i.e. young proteins are richer in intrinsic disorder than the ancient ones. We further noted that young proteins, which are initially poorly connected hubs, prefer to be structurally more disordered than well-connected ancient proteins. The phenomenon strikingly defies the usual trend of well-connected proteins being highly disordered in structure. We justified that structural disorder might help poorly connected young proteins to undergo promiscuous interactions, which provides the foundation for novel protein interactions. The study focuses on the evolutionary perspectives of young proteins in the light of structural adaptations.
Effect of ageing and single nucleotide polymorphisms associated with the risk of aggressive prostate cancer in a New Zealand population.
Vaidyanathan V, Naidu V, Karunasinghe N … +6 more , Kao CH, Pallati R, Jabed A, Marlow G, Kallingappa P, Ferguson LR
Mol Biosyst · 2017 Sep · PMID 28783191 · Publisher ↗
Prostate cancer is one of the most significant male health concerns worldwide, and various researchers carrying out molecular diagnostics have indicated that genetic interactions with biological and behavioral factors pl...
Prostate cancer is one of the most significant male health concerns worldwide, and various researchers carrying out molecular diagnostics have indicated that genetic interactions with biological and behavioral factors play an important role in the overall risk and prognosis of this disease. Single nucleotide polymorphisms are increasingly becoming strong biomarker candidates to identify the susceptibility of individuals to prostate cancer. We carried out risk association of different stages of prostate cancer to a number of single nucleotide polymorphisms to identify the susceptible alleles in a New Zealand population and checked the interaction with environmental factors as well. We identified a number of single nucleotide polymorphisms to have associations specifically to the risk of prostate cancer and aggressiveness of the disease, and also certain single nucleotide polymorphisms to be vulnerable to the reported behavioral factors. We have addressed "special" environmental conditions prevalent in New Zealand, which can be used as a model for a bigger worldwide study.
Global DNA dynamics of 8-oxoguanine repair by human OGG1 revealed by stopped-flow kinetics and molecular dynamics simulation.
Lukina MV, Koval VV, Lomzov AA … +2 more , Zharkov DO, Fedorova OS
Mol Biosyst · 2017 Sep · PMID 28770925 · Publisher ↗
The toxic action of different endogenous and exogenous agents leads to damage in genomic DNA. 8-Oxoguanine is one of the most often generated and highly mutagenic oxidative forms of damage in DNA. Normally, in human cell...
The toxic action of different endogenous and exogenous agents leads to damage in genomic DNA. 8-Oxoguanine is one of the most often generated and highly mutagenic oxidative forms of damage in DNA. Normally, in human cells it is promptly removed by 8-oxoguanine-DNA-glycosylase hOGG1, the key DNA-repair enzyme. An association between the accumulation of oxidized guanine and an increased risk of harmful processes in organisms was already found. However, the detailed mechanism of damaged base recognition and removal is still unclear. To clarify the role of active site amino acids in the damaged base coordination and to reveal the elementary steps in the overall enzymatic process we investigated hOGG1 mutant forms with substituted amino acid residues in the enzyme base-binding pocket. Replacing the functional groups of the enzyme active site allowed us to change the rates of the individual steps of the enzymatic reaction. To gain further insight into the mechanism of hOGG1 catalysis a detailed pre-steady state kinetic study of this enzymatic process was carried out using the stopped-flow approach. The changes in the DNA structure after mixing with enzymes were followed by recording the FRET signal using Cy3/Cy5 labels in DNA substrates in the time range from milliseconds to hundreds of seconds. DNA duplexes containing non-damaged DNA, 8-oxoG, or an AP-site or its unreactive synthetic analogue were used as DNA-substrates. The kinetic parameters of DNA binding and damage processing were obtained for the mutant forms and for WT hOGG1. The analyses of fluorescence traces provided information about the DNA dynamics during damage recognition and removal. The kinetic study for the mutant forms revealed that all introduced substitutions reduced the efficiency of the hOGG1 activity; however, they played pivotal roles at certain elementary stages identified during the study. Taken together, our results gave the opportunity to restore the role of substituted amino acids and main "damaged base-amino acid" contacts, which provide an important link in the understanding the mechanism of the DNA repair process catalyzed by hOGG1.
Insights into the Giardia intestinalis enolase and human plasminogen interaction.
Aguayo-Ortiz R, Meza-Cervantez P, Castillo R … +3 more , Hernández-Campos A, Dominguez L, Yépez-Mulia L
Mol Biosyst · 2017 Sep · PMID 28770921 · Publisher ↗
Giardia intestinalis is an intestinal parasite that causes diarrhea in humans and animals worldwide. The enolase of G. intestinalis (GiENO) participates in its glycolysis pathway and is abundantly expressed in the parasi...
Giardia intestinalis is an intestinal parasite that causes diarrhea in humans and animals worldwide. The enolase of G. intestinalis (GiENO) participates in its glycolysis pathway and is abundantly expressed in the parasite cytosol; however, its localization on the surface of trophozoites and cysts has been demonstrated. Enolases from bacteria and parasites can have different functions and are considered moonlighting proteins, for example, as a cell surface plasminogen receptor. In relation to GiENO, no studies have been performed about its possible participation as a plasminogen receptor. In this work, we employed molecular docking and multiscale molecular dynamics (MD) simulations to explore the possible interactions of human plasminogen (HsPLG) with the open and closed GiENO conformations. Our proposed GiENO plasminogen binding site (PLGBs) was identified at Lys266 based on the sequence comparison with bacterial enolase known to act as a plasminogen receptor. Our docking results performed with multiple MD snapshots of the closed GiENO conformation showed that Lys266 preferentially binds to the K5 domain of HsPLG. On the other hand, open GiENO conformations from all-atom and coarse-grained simulations indicated a high preference of the HsPLG K4 domain for lysine residues 186 and 188. Furthermore, we identified a potential N-glycosylation site of GiENO which suggests a possible explanation for the parasite cell surface localization or host mucin oligosaccharide adhesion mechanism. Our study constitutes the first multiscale computational study to explore the plasminogen receptor function of GiENO for its further consideration as a potential therapeutic target for giardiasis treatment.
Coarse-grained simulations of conformational changes in the multidrug efflux transporter AcrB.
Jewel Y, Liu J, Dutta P
Mol Biosyst · 2017 Sep · PMID 28770910 · Full text
The multidrug resistance (MDR) system actively pumps antibiotics out of cells causing serious health problems. During the pumping, AcrB (one of the key components of MDR) undergoes a series of large-scale and proton-moti...
The multidrug resistance (MDR) system actively pumps antibiotics out of cells causing serious health problems. During the pumping, AcrB (one of the key components of MDR) undergoes a series of large-scale and proton-motive conformational changes. Capturing the conformational changes through all-atom simulations is challenging. Here, we implement a hybrid coarse-grained force field to investigate the conformational changes of AcrB in the porter domain under different protonation states of Asp407/Asp408 in the trans-membrane domain. Our results show that protonation of Asp408 in monomer III (extrusion) stabilizes the asymmetric structure of AcrB; deprotonation of Asp408 induces clear opening of the entrance and closing of the exit leading to the transition from extrusion to access state. The structural changes in the porter domain of AcrB are strongly coupled with the proton translocation stoichiometry in the trans-membrane domain. Moreover, our simulations support the postulation that AcrB should adopt the symmetric resting state in a substrate-free situation.
Effects of threshold on the topology of gene co-expression networks.
Couto CMV, Comin CH, Costa LDF
Mol Biosyst · 2017 Sep · PMID 28770908 · Publisher ↗
Several developments regarding the analysis of gene co-expression profiles using complex network theory have been reported recently. Such approaches usually start with the construction of an unweighted gene co-expression...
Several developments regarding the analysis of gene co-expression profiles using complex network theory have been reported recently. Such approaches usually start with the construction of an unweighted gene co-expression network, therefore requiring the selection of a suitable threshold defining which pairs of vertices will be connected. We aimed at addressing such an important problem by suggesting and comparing five different approaches for threshold selection. Each of the methods considers a respective biologically-motivated criterion for electing a potentially suitable threshold. A set of 21 microarray experiments from different biological groups was used to investigate the effect of applying the five proposed criteria to several biological situations. For each experiment, we used the Pearson correlation coefficient to measure the relationship between each gene pair, and the resulting weight matrices were thresholded considering several values, generating respective adjacency matrices (co-expression networks). Each of the five proposed criteria was then applied in order to select the respective threshold value. The effects of these thresholding approaches on the topology of the resulting networks were compared by using several measurements, and we verified that, depending on the database, the impact on the topological properties can be large. However, a group of databases was verified to be similarly affected by most of the considered criteria. Based on such results, it can be suggested that when the generated networks present similar measurements, the thresholding method can be chosen with greater freedom. If the generated networks are markedly different, the thresholding method that better suits the interests of each specific research study represents a reasonable choice.
Functional aqueous droplet networks.
Booth MJ, Restrepo Schild V, Downs FG … +1 more , Bayley H
Mol Biosyst · 2017 Aug · PMID 28766622 · Publisher ↗
Droplet interface bilayers (DIBs), comprising individual lipid bilayers between pairs of aqueous droplets in an oil, are proving to be a useful tool for studying membrane proteins. Recently, attention has turned to the e...
Droplet interface bilayers (DIBs), comprising individual lipid bilayers between pairs of aqueous droplets in an oil, are proving to be a useful tool for studying membrane proteins. Recently, attention has turned to the elaboration of networks of aqueous droplets, connected through functionalized interface bilayers, with collective properties unachievable in droplet pairs. Small 2D collections of droplets have been formed into soft biodevices, which can act as electronic components, light-sensors and batteries. A substantial breakthrough has been the development of a droplet printer, which can create patterned 3D droplet networks of hundreds to thousands of connected droplets. The 3D networks can change shape, or carry electrical signals through defined pathways, or express proteins in response to patterned illumination. We envisage using functional 3D droplet networks as autonomous synthetic tissues or coupling them with cells to repair or enhance the properties of living tissues.
MALDI MS imaging investigation of the host response to visceral leishmaniasis.
Jaegger CF, Negrão F, Assis DM … +9 more , Belaz KRA, Angolini CFF, Fernandes AMAP, Santos VG, Pimentel A, Abánades DR, Giorgio S, Eberlin MN, Rocha DFO
Mol Biosyst · 2017 Sep · PMID 28758666 · Publisher ↗
Mass spectrometry imaging (MSI) of animal tissues has become an important tool for in situ molecular analyses and biomarker studies in several clinical areas, but there are few applications in parasitological studies. Le...
Mass spectrometry imaging (MSI) of animal tissues has become an important tool for in situ molecular analyses and biomarker studies in several clinical areas, but there are few applications in parasitological studies. Leishmaniasis is a neglected tropical disease, and experimental mouse models have been essential to evaluate pathological and immunological processes and to develop diagnostic methods. Herein we have employed MALDI MSI to examine peptides and low molecular weight proteins (2 to 20 kDa) differentially expressed in the liver during visceral leishmaniasis in mice models. We analyzed liver sections of Balb/c mice infected with Leishmania infantum using the SCiLS Lab software for statistical analysis, which facilitated data interpretation and thus highlighted several key proteins and/or peptides. We proposed a decision tree classification for visceral leishmaniasis with distinct phases of the disease, which are named here as healthy, acute infection and chronic infection. Among others, the ion of m/z 4963 was the most important to identify acute infection and was tentatively identified as Thymosin β4. This peptide was previously established as a recovery factor in the human liver and might participate in the response of mice to Leishmania infection. This preliminary investigation shows the potential of MALDI MSI to complement classical compound selective imaging techniques and to explore new features not yet recognized by these approaches.
2,5-Hexanedione induces autophagic death of VSC4.1 cells via a PI3K/Akt/mTOR pathway.
Guan H, Piao H, Qian Z … +5 more , Zhou X, Sun Y, Gao C, Li S, Piao F
Mol Biosyst · 2017 Sep · PMID 28752163 · Publisher ↗
2,5-Hexanedione (HD) is an important bioactive metabolite of n-hexane, which mediates the neurotoxicity of the parent compound. Increasing evidence suggests that over-activated autophagy can lead to autophagic neuronal d...
2,5-Hexanedione (HD) is an important bioactive metabolite of n-hexane, which mediates the neurotoxicity of the parent compound. Increasing evidence suggests that over-activated autophagy can lead to autophagic neuronal death; however, whether the excessive autophagy is involved in HD-induced neurotoxicity remains unknown. To investigate the effect of HD on autophagy and to find its underlying mechanism, we respectively treated VSC4.1 cells with 5, 15 and 25 mM HD for 24 h. Our results show that HD induced excessive autophagy of VSC4.1 cells in a dose-dependent manner, also, the over-activated autophagy was significantly mitigated in the presence of PI3K activator or Akt activator or mTOR activator. These results indicate that HD induces excessive autophagy of VSC4.1 cells by repressing the PI3K/Akt/mTOR signaling pathway. LDH assay showed that HD contributed to a concentration dependent increase in VSC4.1 cell death, which was significantly reduced by the administration of PIK-III, an autophagy inhibitor. These results also indicate that HD induces autophagic death of VSC4.1 cells via the signaling pathway.
Systems-level organization of non-alcoholic fatty liver disease progression network.
Shubham K, Vinay L, Vinod PK
Mol Biosyst · 2017 Aug · PMID 28745372 · Publisher ↗
Non-Alcoholic Fatty Liver Disease (NAFLD) is a complex spectrum of diseases ranging from simple steatosis to Non-Alcoholic Steatohepatitis (NASH) with fibrosis, which can progress to cirrhosis and hepatocellular carcinom...
Non-Alcoholic Fatty Liver Disease (NAFLD) is a complex spectrum of diseases ranging from simple steatosis to Non-Alcoholic Steatohepatitis (NASH) with fibrosis, which can progress to cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is complex, involving crosstalk between multiple organs, cell-types, and environmental and genetic factors. Dysfunction of the adipose tissue plays a central role in NAFLD progression. Here, we analysed transcriptomics data obtained from the Visceral Adipose Tissue (VAT) of NAFLD patients to understand how the VAT metabolism is altered at the genome scale and co-regulated with other cellular processes during the progression from obesity to NASH with fibrosis. For this purpose, we performed Weighted Gene Co-expression Network Analysis (WGCNA), a method that organizes the disease transcriptome into functional modules of cellular processes and pathways. Our analysis revealed the coordination of metabolic and inflammatory modules (termed "immunometabolism") in the VAT of NAFLD patients. We found that genes of arachidonic acid, sphingolipid and glycosphingolipid metabolism were upregulated and co-expressed with genes of proinflammatory signalling pathways and hypoxia in NASH/NASH with fibrosis. We hypothesize that these metabolic alterations might play a role in sustaining VAT inflammation. Furthermore, immunometabolism related genes were also co-expressed with genes involved in Extracellular Matrix (ECM) degradation. Our analysis indicates that upregulation of both ECM degrading enzymes and their inhibitors (incoherent feedforward loop) potentially leads to the ECM deposition in the VAT of NASH with fibrosis patients.
Expediting dynamics approach to understand the influence of 14-3-3ζ causing metastatic cancer through the interaction of YAP1 and β-TRCP.
D K, Ramireddy S, P R … +1 more , C S
Mol Biosyst · 2017 Sep · PMID 28745364 · Publisher ↗
The 14-3-3ζ protein acts as a molecular switch in regulating the TGF-β pathway, which alters from a tumor suppressor in the early stage of breast cancer to a promoter of metastasis in the late stage. This change is due t...
The 14-3-3ζ protein acts as a molecular switch in regulating the TGF-β pathway, which alters from a tumor suppressor in the early stage of breast cancer to a promoter of metastasis in the late stage. This change is due to the binding of 14-3-3ζ with YAP1 and β-TRCP in premalignant and cancer cells, respectively. Owing to this inappropriate role of 14-3-3ζ when involved in cancer and metastasis, we predicted that Gln15, Glu17, Tyr211, and Gln219 are hotspot residues of 14-3-3ζ during its interaction with YAP1 protein. Similarly, we identified Gln15, Tyr211, Leu216, and Leu220 as hotspot residues of 14-3-3ζ during its interaction with β-TRCP protein. Targeting these residues of 14-3-3ζ can prevent cancer and metastasis caused by malfunctioning of the TGF-β pathway. In this work, we also predicted that YAP1 is an intrinsically disordered protein (IDP), and such proteins bind with other proteins via either an induced fit or a conformational selection mechanism. Intuitively, we found that 14-3-3ζ has high affinity towards phosphorylated YAP1 at Ser127 rather than unphosphorylated YAP1, which is in close agreement with previously reported experimental works. Thus, we performed an analysis by molecular dynamics simulations to reveal the conformational changes in YAP1 after phosphorylation at the atomistic level. Our work clearly illustrates the effect of phosphorylation on YAP1 in terms of conformational changes and the regulation of its function.
System analysis identifies distinct and common functional networks governed by transcription factor ASCL1, in glioma and small cell lung cancer.
Donakonda S, Sinha S, Dighe SN … +1 more , Rao MRS
Mol Biosyst · 2017 Jul · PMID 28742165 · Publisher ↗
ASCL1 is a basic Helix-Loop-Helix transcription factor (TF), which is involved in various cellular processes like neuronal development and signaling pathways. Transcriptome profiling has shown that ASCL1 overexpression p...
ASCL1 is a basic Helix-Loop-Helix transcription factor (TF), which is involved in various cellular processes like neuronal development and signaling pathways. Transcriptome profiling has shown that ASCL1 overexpression plays an important role in the development of glioma and Small Cell Lung Carcinoma (SCLC), but distinct and common molecular mechanisms regulated by ASCL1 in these cancers are unknown. In order to understand how it drives the cellular functional network in these two tumors, we generated a gene expression profile in a glioma cell line (U87MG) to identify ASCL1 gene targets by an si RNA silencing approach and then compared this with a publicly available dataset of similarly silenced SCLC (NCI-H1618 cells). We constructed TF-TF and gene-gene interactions, as well as protein interaction networks of ASCL1 regulated genes in glioma and SCLC cells. Detailed network analysis uncovered various biological processes governed by ASCL1 target genes in these two tumor cell lines. We find that novel ASCL1 functions related to mitosis and signaling pathways influencing development and tumor growth are affected in both glioma and SCLC cells. In addition, we also observed ASCL1 governed functional networks that are distinct to glioma and SCLC.
Protein stability and dynamics influenced by ligands in extremophilic complexes - a molecular dynamics investigation.
Khan S, Farooq U, Kurnikova M
Mol Biosyst · 2017 Aug · PMID 28737816 · Publisher ↗
In this study, we explore the structural and dynamic adaptations of the Tryptophan synthase α-subunit in a ligand bound state in psychrophilic, mesophilic and hyperthermophilic organisms at different temperatures by MD s...
In this study, we explore the structural and dynamic adaptations of the Tryptophan synthase α-subunit in a ligand bound state in psychrophilic, mesophilic and hyperthermophilic organisms at different temperatures by MD simulations. We quantify the global and local fluctuations in the 40 ns time scale by analyzing the root mean square deviation/fluctuations. The distinct behavior of the active site and loop 6 is observed with the elevation of temperature. Protein stability relies more on electrostatic interactions, and these interactions might be responsible for the stability of varying temperature evolved proteins. The paper also focuses on the effect of temperature on protein dynamics and stability governed by the distinct behavior of the ligand associated with its retention, binding and dissociation over the course of time. The integration of principle component analysis and a free energy landscape was useful in identifying the conformational space accessible to ligand bound homologues and how the presence of the ligand alters the conformational and dynamic properties of the protein.
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